Cell-based assays offer a powerful platform for quantifying modulation of cellular targets by small molecule synthetic compounds or biomolecules. These assays run in physiologically relevant conditions allowing concurrent evaluation of cell-permeability, toxicity, and target specificity, significantly increasing the quality and quantity of successful lead compounds. In addition, cell lines are useful for expression of recombinant proteins and production of antibodies for research and clinical purposes. Cell culture in the drug discovery field has evolved over the years from traditional 2D monolayer cell lines to more complex 3D cell lines that more closely mimic in vivo cell environments. With the advancements in cell-based analysis there has been an increase in innovations that improve throughput through automation.
The current trend towards automation of cell culture, manipulation, and cell-based assay development involves separate systems that are modular and can work with different cell lines and assay readouts:
- For cell culture maintenance, sterile boxes with increasing complexities and footprints allow for full automation of cell maintenance workflows. Coupled with incubators and centrifuges, these set-ups are essential for maintaining sterility of cell lines and simplify staffing concerns.
- Automation of cell-based assays is possible using liquid handlers that can be set up to dispense to high-density assay formats such as 384 and 1536 arrays, further increasing throughput and reproducibility. These high-density assays also minimize the number of cells needed, thus reducing reagent cost and consumption.
- Single cell analysis recognizes the heterogeneity of cells and gives unique insight to disease pathology progressing drug design and discovery. Innovative technologies integrating microfluidics in the design of liquid dispensers has paved way for increased throughput in this field by simplifying single cell dispensing into high-density well plates.
- Finally, a variety of automated assay readout systems are available ranging from live imaging systems, flow cytometry to luminescence and fluorescence assays.
Overall, these separate systems have led to an increase in throughput and efficiency. However, practical implementation of cell-based high-throughput screening is still a challenge. Phenotypic readouts require long incubation periods with compounds of interest. Additionally, commonly used biochemical strategies that report on specific activities are incompatible with cellular physiological conditions. Label-free technologies such as mass spectrometry (MS) allow for target-specific readouts on whole cells or lysates, dramatically shortening assay workflows. High-content screening (HCS) has had a resurgence as a high-throughput cell-based assay with an increase in available instrumentation. Cellular imaging techniques or MS are used to identify distinct phenotypic fingerprints in treated vs control cells. The large and complex datasets generated by HCS are well-suited for computational analysis using machine learning algorithms, accelerating data analysis workflows.
Given the forward momentum of automation and increase in throughput today, we expect further technological innovations in the coming years to define cell-based assays as a staple technique in high-throughput analysis.