# A cell-cycle induced genetic recorder for simultaneous recovery of cell divisions and lineage

> **NIH NIH R21** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $297,248

## Abstract

Project Summary
Revealing the lineage relations among cells has the potential to illustrate evolutionary patterns in tumor initiation
and resistance to therapies and shed light on the processes which give rise to developmentally complex
organisms. However, studying these relationships in cancer biology and developmental biology is currently
limited by the difficulty of cell lineage tracing and reconstruction in-vivo. Complete reconstructions of cell lineages
require non-invasive live cell imaging, which is restricted to relatively small numbers of cells and impractical for
physiologically-relevant studies. Although recent systems for CRISPR-mediated genome barcoding have
emerged as a promising alternative, they suffer limitations in the diversity and generation rate of lineage-
identifying information which render them unsuited to studies of clonal evolution and lineage development,
especially in cancer. Moreover, these methods fail to explicitly capture cell divisions, a basic parameter of
somatic evolution which could impact our understanding of a cancer's response to intervention.
To improve recovery of population dynamics and cell lineage information from cancer models, we propose a cell-
cycle inducible genetic construct that will record, in a single locus, the sequence of divisions and lineage of each
cell. Our approach uses cell-cycle regulated ubiquitination to control the activity of a donor-free CRISPR-based
genome recording device which barcodes cells upon each division. In this study, we will evaluate the ability of
our device to track lineage information and cell division dynamics in clonal human and mouse cell populations.
To demonstrate its investigative potential in developmental studies, we will combine our cell-division barcoding
strategy with single-cell RNA sequencing to identify healthy and abnormal differentiation in cancer- and hiPSC-
derived organoids. If successful, our improvements to recovery of cell division, clonality, and lineage will improve
our understanding of development, explain evolutionary sources of resistance in cancer, and guide practitioners
toward more effective treatments in translational research.

## Key facts

- **NIH application ID:** 10358198
- **Project number:** 1R21CA257980-01A1
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ANGELA M. BELCHER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $297,248
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358198

## Citation

> US National Institutes of Health, RePORTER application 10358198, A cell-cycle induced genetic recorder for simultaneous recovery of cell divisions and lineage (1R21CA257980-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10358198. Licensed CC0.

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