The National Science Foundation (NSF) Division of Chemical, Bioengineering, Environmental and Transport Systems (CBET), seeks 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 robust and reproducible set of differentiation design rules, predictive models, real-time sensing, control, and quality assurance methods, and integrate them into a workable differentiation strategy. They must develop a fundamental understanding of how cells develop, including mechanisms, molecular machinery, dynamics, and cell-cell interactions, and use this understanding to manipulate cells purposefully. Investigators can choose any undifferentiated cell type, from any animal species, as a starting point and choose any appropriate functional product (cell, organoid, etc.) with real-world relevance. This solicitation parallels NSF's investment in Understanding the Rules of Life (URoL): Predicting Phenotype, NSF's Big Idea focused on predicting the set of observable characteristics (phenotype) of an organism based on its genetic makeup and the nature of its environment and applies it to understanding and accomplishing the intentional and guided differentiation of an undifferentiated cell into cells, organoids or tissues with predetermined activities and functions.
The process of differentiation involves a multiplex combination of signaling molecules, receptors, promoters, markers, and 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 still cannot engineer stem cells to allow for synthetic induction of differentiation along a predetermined path that can be actively monitored and manipulated on-the-fly. Such control of differentiation will enable the realization of individualized medicine in areas such as regenerative medicine, cancer treatment with engineered killer cells, the development of functional cells and tissues to treat disease, 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 developmental biology, stem cell biology, cell biology, engineering, synthetic and systems biology, computation, sensing, and physics. 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 of the mechanisms that underlie developmental processes. Collaborative proposals, of a duration up to 4 years, with budgets between $1,000,000 to $1,500,000 total will be considered. Proposed budgets must be justified by project scope and need for complementary expertise. The solicitation will support teams of three or more PI/co-PIs and senior personnel. Proposals with only one PI or one PI with one other senior personnel are not permitted. Reflecting the need for thoughtful collaboration and planning required for these projects, Letters of Intent are required to be submitted prior to submission of a full proposal.