Better health diagnostics through genetically engineered embedded sentinel cells

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Cells can now be genetically programmed to record their histories within their genomes, a development that could revolutionize the study of developmental and disease processes, according to a collaborative work by researchers from multiple institutions including the University of California, Los Angeles and University of Washington, Seattle.

Non-invasive monitoring of basic physiological variables through methods such as urine or blood sampling offers a signal of processes occurring somewhere in the body. Additional testing of tissue samples and clinical assessments are then used to diagnose or treat based on the evidence that further testing can offer.

A fundamental challenge in research is explaining biological states or processes in terms of preceding events. Cellular histories encompass lineage relationships, extrinsic influences, internal states, and spatial contexts over time.

Methods for obtaining these histories face reliability limitations due to selection bias, scalability and the destructive nature of some measurement techniques, essentially allowing researchers to see only snapshots of the current state of a cell without a history of how it got there. Traditionally, this requires multiple snapshots over time to construct an evolution of events, with each snapshot facing similar selection bias limitations.

Techniques such as site-specific recombinases, CRISPR systems, and other genome-editing technologies allow cells to write information into their genomes. Recent advances in single-cell and spatial omics technologies enable the recovery of this recorded information.

Having access to recorded molecular and physiological states over time in individuals would provide rich datasets that enable early diagnosis, improved treatment of disease and better-informed health decisions, as well as insight into mechanisms and causes of disease.

The Perspective, "The lives of cells, recorded," published in Nature Reviews Genetics, discusses how recent advances in genome engineering enable DNA-based recording with the potential to create engineered "memory sentinel cells."

Sentinel cells could be engineered to capture a diverse range of molecular and cellular biomarkers and then express the information as encoded proteins or nucleic acids which could be retrieved from urine, blood or stool samples.

By locating these sentinel cells at different sites within the body, tissue-specific data could be stored and gathered, complete with current state, extracellular biomarkers and longitudinal cellular histories. This avoids the cell selection bias as the reporting cells would always be from the same tissue population.

Depending on location and data collection type, this could enable insights into developmental processes, disease progression, immune system and microbial responses in diverse biological contexts.

The article suggests several pathways and considerations in developing sentinel cells.

Engineering patient cells to function as sentinel cells to minimize immune rejection risks and ensure compatibility and long-term functionality within the patient's body.

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Sentinel cells could be genetically programmed to record internal signals into their genomes using genome-editing tools like CRISPR systems that allow cells to write information into their DNA. This DNA recording enables long-term storage and accurate replication of information across multiple cell divisions.

Engineering the cells to produce secreted information-rich proteins or nucleic acids that can be detected non-invasively.

Incorporating small-molecule-activated kill switches that can eliminate the sentinel cells if necessary.

The study proposes engineering sentinel cells by genetically modifying autologous cells to record internal molecular and physiological signals directly into their genomes using DNA-based recording systems like CRISPR. These cells would reside throughout the body, continuously capturing data over extended periods. To retrieve this information non-invasively, the cells would be designed to secrete specific proteins or nucleic acids detectable in bodily fluids. Secreted information (recorded in DNA or RNA form) must eventually be recovered by sequencing methods.

By integrating programmable logic circuits, sentinel cells could analyze the recorded data to execute complex, context-specific responses, such as targeting diseased tissues or modulating immune functions. Safety mechanisms like tumor suppressor genes and self-destruct circuits could be incorporated to address potential risks.

Sentinel cells have already been engineered to some degree. One example involves engineering bacteria to act as sentinel cells within the mouse gut. Researchers modified Escherichia coli using a chimeric Cas1–Cas2 reverse transcriptase system to record their global transcriptional responses during gut transit.

These engineered bacteria reverse-transcribed their cellular mRNA and integrated the resulting DNA into their genomes. By analyzing fecal samples through RNA sequencing, scientists recovered the recordings and gained insights into bacterial adaptation to nutrient availability, acid stress, inflammation, and interactions with other microbes. This approach illustrates how sentinel cells can non-invasively monitor complex physiological and environmental conditions in vivo.

Another example is the COURIER system, where cells were engineered to export RNA barcodes packaged into protective nanoparticles. Sampling these exported RNAs from culture media enabled longitudinal tracking of clonal population dynamics without destroying the cells. This method allowed researchers to monitor thousands of distinct cell clones over time, providing valuable data on cellular responses to drug treatments.

These instances demonstrate initial steps toward developing sentinel cells capable of recording and reporting molecular and physiological states within living organisms.

More information: Amjad Askary et al, The lives of cells, recorded, Nature Reviews Genetics (2024). DOI: 10.1038/s41576-024-00788-w

Journal information: Nature Reviews Genetics

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