# Designing complex living systems for monitoring and responding to disease progression

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2021 · $23,974

## Abstract

Project Summary
 Cell-based therapies have shown great potential for cancer treatment, but limitations in circuit design
have prevented their applicability to diverse diseases. Current therapeutic cells only respond in a binary way to
relatively high levels of a transient signal; further, gene therapies deliver only one genetic element to cells, which
limits their abilities to perform complex functions and thus their applicability. Developing new types of cell systems
that can respond to diverse biomarkers and enact multiple, independently regulated circuit elements is critical
for expanding the scope of cell therapies.
 The work proposed here aims to design novel sensors, insulator elements, and computational models in
the context of creating systems to modulate inflammation, primarily because chronic inflammation has a
prominent role in the progression of multiple diseases. One aspect of the investigation will explore ways that
cells can integrate inflammatory signals over extended time periods and how cells differentially respond based
on the total signal experienced. The resulting engineered cell sensors could serve as a basis for developing
therapies for chronic inflammation and other diseases with time-dependent biomarkers. Another aspect of the
investigation will explore ways that genetic insulators and anti-silencing methods can be incorporated into
synthetic circuits. Incorporating multiple, differentially-regulated genetic elements onto single circuits is
challenging, as eukaryotic transcription factors can act across long distances. Determining a set of insulators
that do not cross-react with others will help to create a generalizable framework for using insulators in complex
genetic circuits, and help to enable the creation of more complex genetic circuits. Further, since epigenetic
silencing decreases the activity and effectiveness of gene therapies over time, investigating ways to reduce
silencing—through insulators and other genetic modifications—will help to create ways to improve the longevity
of cell and gene therapies. The investigation will also use computational modeling to explore the interplay
between responsive synthetic cells and pharmacokinetics. The model will incorporate inflammatory cell signaling,
synthetic antibody production, and systems-level distribution to guide the design of therapeutic cells that
modulate inflammation. Taken together, the proposed work will help to elucidate methods of cell sensing and
gene regulation, which are critical steps for developing new classes of cell-based therapies.

## Key facts

- **NIH application ID:** 10313018
- **Project number:** 1F32EB030907-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Monica Pearl McNerney
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $23,974
- **Award type:** 1
- **Project period:** 2021-07-01 → 2021-10-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313018

## Citation

> US National Institutes of Health, RePORTER application 10313018, Designing complex living systems for monitoring and responding to disease progression (1F32EB030907-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313018. Licensed CC0.

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