Typesetting: Using DNA as a Historical Record 

Written By Cornell Undergraduate Research Magazine

Written by Naomi Hammerschlag
Edited by Aseel Albokhari

“WA HATH GOD WRUOGT?” read the scientists, leaping in excitement (this was a symbolic message encoded to demonstrate the system’s recording ability, not literal English text inserted into a chromosome). Encoded within the cell’s DNA was a symbolic message inspired by Numbers 23:23, echoing the first telegraphic transmission of the same phrase [1]. Using a “DNA memory device,” known as a DNA typewriter, the researchers successfully recorded this message into the genome, demonstrating that DNA can act as a biological recording medium. 

The DNA typewriter addresses a specific challenge: current technologies for tracking cellular activity have a limited scope and depend on indirect or invasive observation. Techniques such as live-cell fluorescence microscopy, time-series transcriptional profiling, or epistatic analysis each have drawbacks in accuracy, reproducibility, or temporal resolution [2]. The DNA typewriter offers an alternative that allows biological activity to be recorded directly within the genome, avoiding many of these limitations. Because DNA naturally stores genetic information, it also provides a stable, high-fidelity substrate for recording cellular history. 

Photo from dranthonygustin.com. Curated by Kayla Vance (kmv53@cornell.edu)

DNA typewriters allow cells to “write” their own histories by recording developmental changes over time. Scientists create short DNA sequences, or barcodes, that can be inserted into a cell’s genome and later analyzed [2]. In one proof-of-concept study at the Allen Institute, researchers were able to encode more than 4,000 distinct barcodes in different combinations within single cells [1]. These barcodes serve as durable molecular records of a cell’s responses to signals or environmental cues, allowing scientists to trace its lineage and behavior [3,4]. 

Each new genetic insertion adds to the sequence, strengthening the “typewriter” analogy [4]. The system uses a stretch of DNA called DNA Tape, which contains partial CRISPR-Cas9 target sites [4]. Only the first target site is active; the others are truncated at the 5′ end and remain inactive until editing occurs [4]. Prime-editing guide RNAs (pegRNAs) and a prime-editing enzyme work together to insert a short DNA segment called a k-mer, which represents a barcode corresponding to the specific pegRNA in use [5]. When a pegRNA performs an edit, the k-mer is inserted at the active 5′ site, and the newly added sequence activates the next site in the array by restoring its 5′ end [5]. This process repeats cyclically, allowing cells to record a chronological series of edits as they occur [2]. 

Photo from helixomicsanalytics.com. Curated by Kayla Vance (kmv53@cornell.edu)

By sequencing these barcodes, scientists can reconstruct the order of molecular events and identify which pegRNAs were responsible for each edit [2]. Each spacer encoding a unique symbol occupies a defined position along the DNA array—much like the “type guide” of a typewriter, where each symbol corresponds to a single keystroke [2]. 

The DNA typewriter provides a new way to trace how cells change and interact over time, from early development onward. Researchers hope to combine this technology with other lineage-tracing and imaging methods to monitor how cells choose developmental fates and how disruptions in those processes may lead to disease [1]. The tool reimagines DNA not only as a genetic blueprint but also as a chronicle—a living record of the molecular events that shape every cell’s life. 

Naomi Hammerschlag ‘29 is in the College of Arts & Sciences. She can be reached at nh442@cornell.edu.

Cornell Undergraduate Research Magazine
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