Genomes now have the ability to store real-time information about various biological events happening inside living cells, much like a flight data recorder collects data from an aircraft. The innovative method known as ENGRAM is designed to transform cells into historians of their own activities. ENGRAM links different biological signals or events within a cell to a symbolic barcode, allowing for the tracing and archiving of these signals in the genome. This approach can record details like the commands that activate or deactivate genes.
Genomes can now be utilized to retain details of transient biological events within cells in real-time, akin to how a flight data recorder captures information from an airplane.
“Our method, named ENGRAM, aims to transform cells into their own historians,” explained Dr. Jay Shendure, a professor at the University of Washington School of Medicine and scientific director at the Brotman Baty Institute for Precision Medicine. Shendure led the project with Wei Chen, a former graduate student, and Junhong Choi, a former postdoctoral fellow who is now an assistant investigator at Memorial Sloan Kettering Cancer Center in New York.
ENGRAM stands for enhancer-driven genomic recording of transcriptional activity in multiplex, drawing inspiration from a neuroscience term related to memory formation.
A proof-of-concept study showcasing ENGRAM’s capabilities is featured in a publication in Nature on July 17.
“ENGRAM associates each biological signal or event with a symbolic barcode, providing a novel approach to recording that complements existing molecular recording methods,” stated Wei Chen, now a postdoctoral fellow at the UW Medicine Institute for Protein Design.
This innovative strategy tracks and stores the type and timing of biological signals by integrating this data into the genome. For instance, it can monitor the instructions that activate or deactivate genes, offering insights into cell differentiation processes in stem cells and shedding light on cellular functions and their evolutionary impacts.
Shendure acknowledged that creating a record of cellular activities is not a new concept, but traditional methods faced challenges in monitoring multiple signals simultaneously and recording their sequence of occurrence.
Several years ago, Choi, Shendure, and their team overcame some of these hurdles with the DNA Typewriter method, enabling the orderly writing of symbols on DNA strands. However, encoding biological meaning to each symbol remained a challenge.
“DNA Typewriter functions like a keyboard with diverse symbols. With ENGRAM, we tailor those symbols to various biological signals of interest,” Shendure explained.
In the Nature publication, Shendure’s team demonstrated how symbolic recording can monitor the actions of non-coding DNA regions that regulate neighboring gene expression. They illustrated a combination of ENGRAM and DNA Typewriter in identifying cell-type specific activities in numerous gene-regulatory elements.
Some of the monitored regions are involved in gene regulation networks crucial for embryonic development, stress response, immune reactions, and cell survival.
Applying ENGRAM, the researchers continuously recorded mouse stem cells as they formed embryonic organoids in the lab, offering insights into the influences of cellular signaling on embryo development.
“Inspired by advancements in CRISPR technology, both ENGRAM and DNA Typewriter present new opportunities for enhancing genomic recording techniques, potentially capturing the complete cellular history,” Choi remarked.
The scientists developing ENGRAM emphasize the need for further exploration of its capabilities and related genome-based recording technologies.
“This strategy captures biological data within living systems and can be universally applicable across various fields rather than being restricted to specific areas like cancer or neuroscience,” Shendure added.
Shendure highlighted the significance of the research featured in the Nature paper in establishing the Seattle Hub for Synthetic Biology, a collaborative initiative with the Allen Institute, Chan Zuckerberg Initiative, and the University of Washington. This project, led by Shendure, aims to develop technologies for tracing cellular histories over time.
Funding for the study in Nature was provided by grants from the Paul G. Allen Frontiers Group, Alex’s Lemonade Stand Foundation, National Human Genome Research Institute (UM1HG011586, K99HG012973), and the Brotman Baty Institute for Precision Medicine. Shendure is an investigator with the Howard Hughes Medical Institute.
