Reproducible Cells and Organoids via Directed- Differentiation Encoding | 21 532

Opportunity Information: Apply for 21 532

The NSF opportunity "Reproducible Cells and Organoids via Directed-Differentiation Encoding" (Funding Opportunity Number 21-532) supports research teams that can move cell differentiation from an often trial-and-error craft into a reproducible, controllable, and mechanistically grounded process. The core goal is to figure out how to reliably direct undifferentiated cells into mature, functional cells or organoids, and to do it in a way that produces repeatable outcomes across runs, labs, and conditions. NSF is not simply looking for a new differentiated cell type or a novel organoid. The emphasis is on building a validated, transferable set of "design rules" and mechanistic models for differentiation, paired with real-time sensing, feedback control, and quality assurance methods that together form a practical and usable differentiation strategy.

Projects must deepen fundamental understanding of development and differentiation, including the molecular machinery and dynamics that govern fate decisions, as well as how cells interact with each other and with the extracellular matrix (ECM). The solicitation highlights that differentiation is driven by many coupled variables at once, including signaling molecules, receptors, promoters, markers, and both chemical and mechanical regulators. While the field has identified individual factors that can push cells toward certain fates, NSF is pointing to a major gap: we still do not adequately understand how combinations of biochemical and environmental cues work together to reliably steer cells along a predetermined path, nor do we have sufficient capability to monitor that path as it unfolds and actively correct it when it drifts. Responsive proposals therefore need to address differentiation as a dynamic, multiplex, and controllable process rather than a single-factor intervention.

A notable feature of this program is its openness in biological starting points and end products. Investigators may choose any undifferentiated cell type from any animal species, including non-model organisms, and they can target any functional product (a specialized cell type, an organoid, or other relevant differentiated outcome) as long as it has real-world relevance. What matters most is that the chosen system enables the team to uncover generalizable mechanisms and encode them into robust differentiation rules and strategies that can be validated and reproduced.

NSF frames the broader impacts as both foundational and enabling. On the basic science side, deterministic control over differentiation could answer long-standing mechanistic questions about how specific cells, tissues, and organs achieve their physiological function, and it could clarify processes tied to symbiosis, disease progression, and immune responses to infection. On the applied side, better control and reproducibility would support advances in biomanufacturing and the creation of new biomaterials, improve individualized medicine, strengthen environmental control and monitoring and adaptive sensing, and make 3D organoids more scalable and consistent for drug testing. In short, the program is motivated by the idea that reproducible differentiation is a missing piece that limits both discovery and translation.

The solicitation is explicitly interdisciplinary and expects convergence across engineering and biology. NSF encourages teams that combine expertise in areas such as engineering design, computation and modeling, sensing and measurement, systems and synthetic biology, developmental and stem cell biology, mechanobiology, cell physiology, microbiology, immunology, and biophysics. The team requirement is strict: proposals must involve three or more PIs/co-PIs and senior personnel with complementary expertise. Submissions with only one PI, or one PI plus only one other senior person, are not allowed and will be returned without review. This structure reflects the program's expectation that successful projects will integrate multiple capabilities, such as mechanistic biology, quantitative modeling, instrumentation for real-time monitoring, and control or manufacturing approaches that enforce reproducibility.

Several boundaries are clearly spelled out regarding what does not fit. Proposals are non-responsive if they only address one isolated aspect of differentiation, or if they focus primarily on producing an engineered living product (cells, tissues, organ-on-a-chip systems, organoids) without simultaneously improving understanding and control of the underlying developmental mechanisms and without extracting broader differentiation rules. Similarly, projects that sit cleanly within a single NSF core program, or that examine individual stages or mechanisms in isolation without integrating them into an overarching, validated differentiation strategy, are considered outside the scope.

From a funding and administrative standpoint, NSF anticipates a limited number of awards (listed as 7 expected). Projects may run up to four years, and collaborative proposals with budgets up to $1,500,000 total will be considered, with the explicit expectation that budgets match the project scope and the need for complementary expertise. A preliminary proposal is required before a full proposal can be submitted, reflecting the planning and coordination expected for these multi-investigator efforts. The opportunity is offered as a grant under NSF research and development categories, associated with CFDA numbers 47.041 and 47.074, and was originally posted in late 2020 with an original closing date in May 2021.

• The National Science Foundation in the science and technology and other research and development sector is offering a public funding opportunity titled "Reproducible Cells and Organoids via Directed- Differentiation Encoding" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 47.041, 47.074.
• This funding opportunity was created on Nov 20, 2020.
• Applicants must submit their applications by May 18, 2021. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• The number of recipients for this funding is limited to 7 candidate(s).
• Eligible applicants include: Others (see text field entitled Additional Information on Eligibility for clarification).

Apply for 21 532

[Watch] Creating a grant proposal using the step-by-step wizard inside the applicant portal: