Reproducible Cells and Organoids via Directed-Differentiation Encoding (RECODE)

The National Science Foundation (NSF) Divisions of Chemical, Bioengineering, Environmental and Transport Systems (CBET), Integrative and Organismal Systems (IOS), Molecular and Cellular Biosciences (MCB), and Civil, Mechanical, and Manufacturing Innovation (CMMI) seek proposals that elucidate mechanisms of, and develop strategies to, direct the differentiation of undifferentiated cells into mature, functional cells or organoids. Projects responsive to this solicitation must aim to establish a robustly validated and reproducible set of differentiation design rules, mechanistic models, real-time sensing, control, and quality assurance methods, and integrate them into a workable differentiation strategy. They must deepen our fundamental understanding of how cells develop and differentiate, providing insights into mechanisms, molecular machinery, dynamics, and cell-cell and cell-extracellular matrix (ECM) interactions, and use this understanding to manipulate cells purposefully. Investigators can choose any undifferentiated cell type from any animal species, including those that may be considered non-model organisms, as a starting point and choose any appropriate functional product (cell, organoid, etc.) with real-world relevance. 

The process of differentiation involves a multiplex combination of signaling molecules, receptors, promoters, markers, and chemical and mechanical regulators that dynamically interact to direct cell development and behavior. While individual inducers of native differentiation have been identified and employed to create specialized cell types, we generally lack fundamental understanding of the roles of biochemical and environmental regulators necessary for synthetic induction of differentiation along a predetermined path and the ability to actively monitor and manipulate that path dynamically. Such control of differentiation will be valuable to answer mechanistic questions about basic biological processes that govern physiological function of specific cells, tissues, and organs, as well as mechanisms for processes involved in symbiosis and disease, and immunological responses to infection. The control of differentiation will also enable the realization of enhanced biomanufacturing, leading to novel products, biomaterials, and significant improvements in individualized medicine, environmental control and monitoring, adaptive sensing, as well as the scalable and reproducible application of 3D organoids in drug testing.

The convergence of many disciplines is necessary to answer the fundamental questions and devise the tools needed to realize truly deterministic cell induction and differentiation strategies. As such, investigators are encouraged to form interdisciplinary teams with expertise in engineering, computation, sensing, systems and synthetic biology, developmental biology, stem cell biology, mechanobiology, cell physiology, microbiology, immunology, and biophysics. Proposals will not be responsive to this solicitation if they address only one aspect of the differentiation process or aim to create a functional living product without improving our understanding and control of the mechanisms that underlie developmental processes. Collaborative proposals, of a duration up to 4 years, with budgets up to $1,500,000 total will be considered. Proposed budgets must be justified by the project scope and need for complementary expertise. The solicitation will support teams of three or more PI/co-PIs and senior personnel with complementary expertise. Proposals with only one PI or one PI with one other senior personnel are not permitted and will be returned without review. Reflecting the need for thoughtful collaboration and planning required for these projects, Preliminary Proposals are required to be submitted prior to submission of a full proposal.

Topics that reside clearly within the boundaries of a single NSF core program are outside of the scope of this solicitation. Specifically, projects centered around the exploration of individual stages/mechanisms of differentiation in isolation or production of engineered cells, tissues, organ-on-a-chip systems, or organoids without developing an understanding of differentiation rules are not responsive to this solicitation.