# Synthetic gene sensors and effectors to redirect organoid development

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $682,610

## Abstract

Project Summary
Human induced pluripotent stem cell (hiPSC)-derived organoids hold great promise for tissue engineering and
personalized drug screening, but obtaining the desired multicellular organization and function from these
systems is usually performed in an ad hoc fashion without forward design specification. Recently, we reported
successful liver bud formation containing stromal cells, vascular tube-like structures and hematopoiesis-like
processes by synthetically inducing diversity in GATA6 expression from a single hiPSC population. This
accomplishment suggests that expanding circuit logic operations to artificially control differentiation drivers at
particular bifurcations in lineage specification could profoundly impact the complexity and functionality of
organoids. In this project, we bring together mathematical modeling, machine learning, optimization, and
innovative synthetic biology techniques to elucidate and design fundamental decision and communication rules
for guiding cells into complex, heterogeneous tissues. Our overarching hypothesis is that appropriate timing and
predictable stochastic control of the expression of intracellular and extracellular factors is critical for redirecting
lineage choices in order to elicit desired multicellular organization from a population of differentiating cells. We
will develop synthetic tools for sensing differentiation stages of iPSC-derived organoids and construct and
characterize a stochastic commitment switch in an inducible reporter system. These tools will be integrated in
synthetic gene circuits for engineering emergent multicellular organization through stochastic temporal control
of developmental factors. The modular commitment switches developed in this project will be capable of
exploring how the degree of subpopulation biasing of cell fate decisions and level of cell fate synchronization at
bipotent differentiation stages impacts self-assembly and emergent multicellular organization of an organoid.
Our aims - executed through a closed loop of computational and experimental investigations - will shed insight
on how generalizable methods of controlled manipulation can elicit desired organoid-level emergent properties.

## Key facts

- **NIH application ID:** 10155771
- **Project number:** 1R01EB030946-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Calin Belta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $682,610
- **Award type:** 1
- **Project period:** 2021-05-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155771

## Citation

> US National Institutes of Health, RePORTER application 10155771, Synthetic gene sensors and effectors to redirect organoid development (1R01EB030946-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155771. Licensed CC0.

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