Analyzing Millions of Cells at Scale
Genetic screens are an important tool for linking genes to biological functions. While genome-wide CRISPR screens can efficiently identify genes involved in simple cellular traits, studying more complex characteristics that can only be observed under a microscope has remained challenging. Existing approaches require a trade-off between the scale of a screen and the amount of biological information that can be captured.
The new method, SPARCS, combines microscopy, CRISPR-based genetic screening, machine learning and automated laser microdissection. This enables researchers to screen large populations of genetically modified cells for complex features visible under the microscope and subsequently isolate selected cells with particularly interesting characteristics for further analysis.
In two genome-wide screens, the research team analysed around 70 million cells. SPARCS identified nearly all known genes involved in macroautophagy, a key cellular recycling process. In addition, the researchers discovered a previously undescribed autophagy phenotype associated with the gene EI24.
New Insights into the Innate Immune Response
The researchers also used SPARCS to investigate the regulation of the immune sensor STING. They found that the pH level within the Golgi apparatus plays an important role in early STING trafficking and activation. The genes GPR89A and GPR89B, which encode the protein GPHR, contribute to maintaining the acidic environment of the Golgi. When this balance is disrupted, STING activation is impaired. The findings suggest a previously unknown mechanism regulating STING signaling.
Linking Imaging with Molecular Profiling
Because SPARCS physically isolates selected cells, the method can also be combined with further molecular analyses. In the study, the researchers coupled SPARCS with mass spectrometry-based proteomics, allowing them to link image-based cellular characteristics with changes at the protein level. This combination of imaging, genetic screening and molecular profiling opens up new possibilities for systematically investigating the genetic and molecular mechanisms underlying complex cellular phenotypes.
Original Publication
Schmacke et al., 2026: SPARCS enables scalable recovery of complex image-based phenotypes for genetic screening. Cell. DOI: 10.1016/j.cell.2026.09.021
