Cells are miniature laboratories that allow scientists to study key biological processes. Thus, they may provide a more natural way to assess the in vivo effects of drugs.
According to Visiongain, the market for cell-based assays exceeded $2 billion in 2012, and is predicted to quadruple to $8 billion by 2022.
New developments in this arena include getting back to basics by utilizing phenotypic screening for drug development. Additionally, employing patient cells and differentiating stem cells into defined cellular lineages are emerging as key strategies for assessing therapeutic responses. Technological advances include novel approaches for tackling the barrier of how to differentiate stem cells into specific cell types as well as integrating the speed and multiparameter assessments of flow cytometry with digital microscopy to perform phenotypic and functional analyses simultaneously.
Despite the rapid advances and focus on target-based drug discovery, the lion’s share of new first-in-class small molecule drugs (approved 1999–2008) were identified using the earlier method of phenotypic screening, notes Gary Allenby, Ph.D., business director at Aurelia Bioscience, a bioassay screening and development CRO in the U.K.
“Some compare phenotypic drug discovery versus target-based drug discovery as serendipity versus constrained research. In reality, examining the pharmacological properties of the same compound in different assays can allow greater insight into the mechanism of action to better understand the target’s biology. We employ a number of different phenotypic assays,” says Dr. Allenby.
“Label-free assays for screening are a very useful example. In the last five years, more investigators have become interested and excited about this technology. We see this as being implemented more and more, especially to differentiate between G-coupled protein receptors (GPCRs). One can measure responses in native or physiologically relevant systems including primary human or animal cells.
“You don’t have to overexpress or amplify via genetic modifications. This is a great help for understanding the molecular pharmacology of a receptor in its natural environment. Also a recombinant system doesn’t necessarily have the natural coupling or even engage the correct signaling pathways. Label-free assays allow measurements such as changes in cell shape, movement, and translocation of proteins into or out of the measurement window (~100 nanometers). The criticism of these assays is that it’s a black-box approach and one doesn’t know if the ligand causes direct or indirect effects.”
Another cell-based assay Aurelia employs is the fluorescent imaging plate reader (FLIPR) technology. “We have employed FLIPR in a range of assay formats, readouts, and targets, including GPCRs. These can be evaluated using fluorescent methodologies in 96-, 384-, and 1,536-well plates,” adds Dr. Allenby.
For the future, Dr. Allenby says that he finds the use of microfluidics combined with label-free cell biological assays to be an intriguing type of cell-based assay. “This would allow much more in-depth exploration of the boundaries of how physiological compounds affect the cell environment.”