Nuclear Hashing Technology Could Reveal How Drugs Interact with Cells

By pooling genetically different cells, a new cell-response screening method known as sci-Plex can reveal what happens to individual cells when the sample is treated, according to a new study at the University of Washington Health Sciences/UW Medicine.

Reported in Science, the study noted how sci-Plex collects information on changes in genetic expression in each labeled cell, providing data useful in exploring mechanism triggered by drugs or other agents.

This technique overcomes several limitations of typical high-throughput chemical screens conducted on cell samples. These screens are commonly used to tray to discover new cancer drugs, and in many other biomedical applications; however, they only give a coarse readout, such as cell survival, or a specific molecular finding.

Due to these extremes, most assays routinely miss subtle gene expressions that may reveal mechanisms triggered inside perturbed cells or may fail to detect nuances that might indicated adverse events of drug being tested.

To address these limitations, a research team developed a more formative technique. This new technology, sci-Plex, improves labelling cell nuclei with an advance in profiling. All of this is done in a single-cell resolution and in a cost-effective manner.

The researchers applied sci-Plex to a screen using 3 kinds of cancer lines, leukemia, lung cancer, and breast cancer, treated with 180 compounds used for cancer, HIV, and autoimmune disease therapies. The cells were labeled with a nuclear hashing of small, single strands of DNA.

This hashing identifies different cells and permits scientists to map which cells received which drug. In just 1 experiment, the researchers measured gene expression in 650,000 single cells from more than 5000 independently treated samples.

The results indicated significant differences in the ways some of the cancer cells reacted to specific compounds. They also revealed shared patterns among cells with regard to other chemical families as well as some properties that distinguished drugs within a chemical family.

In a specific class of cancer drugs, HDAC inhibitors, researchers found that the gene regulatory changes matched the proposition that these inhibitors stopped cancer cell proliferation by blocking access to an energy source.

Overall, the sci-Plex results suggest that it could be scaled to thousands of samples to target diverse biochemical pathways, catalysts, regulators, and modes of action, such as the treatment of disease, understanding the effects of certain drugs, and more.

Furthermore, researchers believe that the sci-Plex could be a usual tool for precision medicine. A distinct advantage of the technology is that it can distinguish how a compound affects subsets of cells. In addition to tumor cells, such subsets could also include lab-dish living models such as reprogrammed cells, organoids, and synthetic embryos.

Reference

• Technique shows how individual cancer cells react to drugs [press release]. UW Medicine website. Published December 6, 2019. https://newsroom.uw.edu/news/technique-shows-how-individual-cancer-cells-react-drugs. Accessed December 11, 2019.