Reproducible Cells and Organoids via Directed- Differentiation Encoding | 21 608

Opportunity Information: Apply for 21 608

The NSF opportunity "Reproducible Cells and Organoids via Directed-Differentiation Encoding" (RECODE; Funding Opportunity Number 21-608) is a multidisciplinary research solicitation aimed at making cell differentiation far more predictable, controllable, and reproducible than it is today. The core idea is to move beyond ad hoc or trial-and-error differentiation protocols and instead build robust, validated "design rules" and mechanistic models that can reliably guide undifferentiated cells into mature, functional cell types or organoids. NSF is explicitly looking for projects that treat differentiation as a dynamic, information-rich process that can be monitored in real time, steered with feedback control, and verified with rigorous quality assurance methods, ultimately producing a practical, end-to-end differentiation strategy that others can reproduce.

A defining feature of this program is that it requires both engineering-style control and deep biological understanding. Successful projects must explain how differentiation decisions arise from the combined effects of signaling molecules and pathways, gene regulatory networks, receptors and promoters, molecular markers, and the chemical and mechanical conditions surrounding cells. NSF wants teams to uncover the underlying mechanisms and molecular machinery that drive development, including how timing and dynamics matter, not just which factors are present. The solicitation also emphasizes the importance of the cellular environment, including cell-cell interactions, cell-microbe interactions, and cell-extracellular matrix (ECM) interactions, and expects proposers to use mechanistic insights about these interactions to intentionally manipulate developmental trajectories rather than simply observe them.

The program is deliberately broad in terms of biological starting materials and target outcomes. Investigators may choose any undifferentiated cell type from any animal species, including human cells, and may aim for any functional product that has real-world relevance, whether that product is a mature cell type, a tissue-like assembly, or a 3D organoid. NSF encourages the use of non-model systems (for example, systems other than standard mouse models) and also encourages non-medical targets, signaling that the agency is interested in applications across biotechnology, materials, sensing, and environmental domains, not only regenerative medicine. Functional targets can span many physiological systems, including cardiovascular, nervous, and immune systems, among others.

RECODE is positioned as part of NSF's broader push to build U.S. biotechnology capabilities that support the national bioeconomy. The solicitation highlights why this matters: differentiation is controlled by many interacting biochemical and biophysical regulators, and while researchers can sometimes coax cells toward specific fates, the field still lacks a generalizable, quantitative understanding of how to synthetically induce differentiation along a predetermined path and how to actively track and adjust that path as cells change. NSF is looking for work that can answer fundamental questions about development and physiological function, including questions relevant to immunity and host-microbe relationships (such as how systems move between symbiosis and disease, or how immune responses emerge during infection). At the same time, NSF is clear that better control over differentiation could enable improved biomanufacturing, new biomaterials, more scalable and consistent organoid production for drug testing, and advances in individualized medicine, environmental monitoring, and adaptive sensing.

Because the program is designed around convergence research, team structure and integration are central requirements rather than optional enhancements. NSF encourages interdisciplinary teams that combine expertise spanning engineering, computation, sensing, systems and synthetic biology, developmental biology, stem cell biology, mechanobiology, cell physiology, microbiology, immunology, and biophysics. The solicitation is explicit that proposals will be considered non-responsive if they focus on only one slice of the differentiation problem or if they mainly aim to produce an engineered living product without advancing the underlying understanding and controllability of differentiation. Likewise, projects that sit clearly inside a single traditional NSF core program area, or that focus on isolated stages or mechanisms without building unified differentiation rules and control strategies, are considered outside scope. Work centered purely on building engineered cells, tissues, organ-on-a-chip systems, or organoids without developing broadly useful differentiation rules is also not responsive.

On the funding and submission mechanics, RECODE supports collaborative grants with project durations up to 4 years and budgets up to $1,500,000 total, with the expectation that the budget matches the scope and the need for complementary expertise. NSF anticipates making around 7 awards (as stated in the opportunity record), and the award ceiling is listed as 0 in the summary data even though the solicitation text specifies budgets up to $1.5M, which typically indicates that the cap is managed through the solicitation guidance rather than the system field. A key compliance detail is that proposals must be submitted by teams of three or more PI/co-PIs and senior personnel with complementary expertise; proposals with a single PI, or a PI plus only one additional senior person, are not allowed and will be returned without review. Another structural requirement is that preliminary proposals are mandatory before a full proposal can be submitted, reflecting NSF's expectation that teams will use the preliminary stage to demonstrate cohesive planning and true integration across disciplines.

In short, RECODE is looking for ambitious, team-based projects that treat directed differentiation like a controllable, measurable process: discover and validate generalizable differentiation rules, build mechanistic and predictive models, develop real-time sensing and feedback control, and embed quality assurance to deliver reproducible cells or organoids. The emphasis is not merely on producing a particular cell type or organoid once, but on building the scientific and engineering foundation to do it reliably, transparently, and in a way that can be transferred and scaled across settings and applications.

• 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 Aug 24, 2021.
• Applicants must submit their applications by Mar 31, 2022. (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).

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