Deciphering Disease Progression And Cell Processes With TIGER, In Vivo And Noninvasively

Could patients in the future take a programmed ribonucleic acid-based diagnostic probiotic to analyze their gut health using a single cell? Researchers from the Helmholtz Institute for RNA-based Infection Research (HIRI) and the Julius Maximilian University of Würzburg (JMU) have developed a new technology that they call TIGER. This makes it possible to decode complex processes in single cells in vivo by recording old RNA transcripts. The results were published in the journal Nature Biotechnology on January 5, 2023.

Bacterial and viral infections can cause acute acute symptoms, but also have devastating long-term consequences, such as the development of cancer. Therefore, scientists are looking for new approaches and technologies to better understand the course of the disease and to predict cell and tissue development. Using more precise methods, they analyzed the processes underlying individual cells. One of their goals is to detect changes in gene activity, which in turn can indicate pathological events.

Ribonucleic acid (RNA) makes an important contribution to this understanding. They can indicate genetic activity because only an active gene produces an RNA copy (transcript) in a process called transcription. However, the RNA molecules expressed in the transcript only represent the current state. It has proven difficult to track past cellular events, such as B. bacterial infections in relation to current conditions and to infer future results.

“The identity and behavior of a cell depend not only on the current intracellular composition and extracellular environment, but also on past conditions. We were looking for an efficient method at the single-cell level to look at the past and how it relates to the present,” says Professor Chase Beisel, Chair of Synthetic RNA Biology at the Helmholtz Institute for RNA-based Infection Research. HIRI) in Würzburg and first author of the study.

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In their publication, the authors present a new technological approach that could decisively advance medical diagnostics in the future. Their method, called TIGER, is a way to record the presence of specific RNAs in individual living cells.

"By recording RNA, TIGER links the current cell state with the previous transcription state," explains first author Chunlei Jiao. TIGER can measure relative gene expression, detect differences between individual nucleotides, record multiple transcripts simultaneously, and read single-cell phenomena.

According to Jiao, this method has a clear advantage. "Previous studies could only estimate the previous state of the cell using large amounts of data and computational prediction tools to measure the cell asynchronously over time." document in host cells.

In the future, TIGER can be used to study the transcription history of single cells in living organisms and relate it to the current status quo to decipher complex, in vivo and non-invasive cellular responses. For example, one could imagine taking TIGER probiotics to record and then analyze the condition of the digestive tract, the authors concluded.

TIGER (short for “genetically encoded transcript-derived RNA”) uses reprogrammed tracrRNAs (Rptrs) to record selected cellular transcripts as DNA modifications stored in single living bacterial cells. Rptr was designed to bind to recognized transcripts and convert them into guide RNA.

The guide RNA then directs the Cas9 base editor to target the presented DNA target. The reach of the base publication can then be read by sorting. This technology builds on the results of previous research that led to the development of LEOPARD, an in vitro diagnostic platform.

Additional information: Chunlei Jiao et al., RNA uptake into single bacterial cells using reprogrammed tracrRNA, Nature Biotechnology (2023). DOI: 10.1038/s41587-022-01604-8

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