Programming cell functions and tissue self-organization for precision medicine
Cells as ‘intelligent machines’
“My research on programming cells and tissue self-assembly was inspired during my undergraduate days as a mechanical engineering student at Kyoto University,” says Satoshi Toda. “Mechanical engineering involves constructing mechanical parts, engines, robots and other such structures. During the course I began to wonder whether it would be possible to build biological structures or cells, just like mechanical machines. These ideas led to my doctorate in reconstitution of dynamic cell behaviors such as phagocytosis from the Graduate School of Medicine at Kyoto University, and later a post-doc in “programming multicellular self-organizing structures” at the University of California San Francisco, Center for Systems and Synthetic Biology, between 2015 and 2019. I joined WPI-NanoLSI in October 2019.”
The premise of Toda’s research is that cells are ‘intelligent machines’ with an ‘input’ and ‘output’: Cells can sense and respond to their surroundings using sensors (receptors), information processing (intracellular signaling networks), and actuators (cellular actions). Furthermore, Toda’s model assumes that cells can communicate with each other by sensing and responding. “The cell’s sensing and responding system enables cell-to-cell communication and governs complex multicellular collective behaviors such as tissue development,” explains Toda. “To understand how such biological systems work, my approach is to create bottom-up artificial biological systems that can achieve cell functions. I want to create designer cells that are programmed to sense and respond according to the designer’s requirements.”
In their simplest implementation, designer cells express a synthetic receptor to recognize a user-defined input molecule and activate a user-defined output action. The output controls the cell behavior—for example, specific gene expression to control mechanical properties of the cells to drive spatial organization of cells into 3D tissue structures.
“My research aim includes reconstitution of cell functions by identifying sufficient programs to release the functions and application of such programs to cell-based therapy with user-defined therapeutic actions.”
Strategies for implementing customized cell-to-cell communication
Developing tools and methods to engineer multicellular collective behaviors is critical to achieve the goals of Toda’s research. Unresolved issues include the minimum number of genetic programs required for the self-assembly of complex tissue architectures ; the origin of multicellularity during evolution ; and development of practical methods to build innovative tissues for biomedical applications.
“Ultimately, I want to synthetically engineer cell-to-cell communication in order to program multicellular behavior,” explains Toda. “The challenge for synthetic biology is devising strategies for designing new cell to cell communication networks. We recently reported on the use of Notch-based synthetic cell-cell signaling platform to form multilayered structures by programming cells to send and receive signals; that is, we engineered cell to cell communication that modifies cell adhesion and spatial distribution of cells.”
Circuit design of cell-to-cell communication for self-organization
Diverse synthetic self-organizing multicellular structures
Synthetic self-organization of three-layer structure
Toda says that designing customized cell-to-cell communication will enable scientists to test and validate current models for tissue development and create new, non-natural, useful tissues like robotic design.
Plans for the future
“My expertise is in developing and utilizing molecular tools to manipulate protein dynamics inside or on the surface of cells, so I think one of my main roles in the WPI-NanoLSI project is ‘nano-manipulation’, applying synthetic biology tools to manipulate protein activity locally with nano-probe technology,” says Toda. “In addition to this, I would like to pursue developing synthetic cell to cell communication systems including engineering designer cells for smart medicine—for example engineering therapeutic cells for tissue regeneration. I am looking forward to working with my colleagues at WPI-NanoLSI on this multidisciplinary area of research.”
- Engineering cell–cell communication networks: programming multicellular behaviors. Satoshi Toda, Nicholas W Frankel, Wendell A Lim. Current opinion in chemical biology 52, 31-38 (2019).
- Synthetic development: learning to program multicellular self-organization. Satoshi Toda, Jonathan M Brunger, Wendell A Lim. Current Opinion in Systems Biology 14, 41-49 (2019).
- Programming self-organizing multi-cellular structures with synthetic cell-cell signaling. Satoshi Toda, Lucas R Blauch, Sindy KY Tang, Leonardo Morsut, Wendell A Lim. Science 361, 156-162 (2018).
https://sites.google.com/view/satoshitodalab/home (Lab URL)