Cell-based assays continue to provide powerful tools to fuel drug discovery. However, costly late-stage failures are driving the industry’s search for improved approaches and novel tools for interrogating cells. Throughput, reliability, cost, and physiologic relevance of cellular models for predictive toxicology remain central issues in the field.
Visiongain’s “Cell-Based Assays” conference next month will feature topics ranging from technological advances in cellular models to challenges to traditional drug discovery paradigms. Additionally, presentations will provide the latest developments in stem cell biology and demonstrate how applying engineering/computing principles to living systems could revolutionize the design of new therapies.
“In many ways, progress in the drug discovery industry has been quite disappointing in the last 10 years,” reports Mark Slack, Ph.D., group leader of cellular assays, Evotec.
“The inertia and lack of productivity relate to failures in efficacy, poor clinical translation, and stagnant methodologies. The old one-gene, one-drug paradigm is no longer relevant, giving way to phenotypic approaches, capturing targets in their functional background. The landscape is beginning to change with an emerging paradigm that considers the physiology of diseases and the whole organism.
“We are seeing that high-throughput screening formats are employing more physiologically relevant cellular models including use of primary cells and label-free, nonintrusive methods to interrogate new compounds. One rapidly emerging area is the use of stem cell technologies.
“Because of difficult ethical issues in the generation of such cell lines, landmark work has studied and now demonstrated that it is possible to induce the reversal of somatic tissues into stem cell populations (i.e., induced pluripotent stem cells, or iPSCs).
“We can perform assays from affected patients via iPSC technologies and generate cells expressing the disease phenotype. These will be very useful for drug discovery for specific diseases such as Parkinson and Huntington diseases.”
Another area that has benefitted from technological advances is automated electrophysiology. Tiny patch clamp electrodes are now applied to individual cells in a 384-well format, allowing the screening of tens of thousands of compounds.
“This has been an underexploited target class,” Dr. Slack says. “With the emergence of automated patch-clamp assays, a major bottleneck was overcome. However, we now need to deal with the high cost per data point and the relatively low throughput and efficiency of the devices.”
According to Dr. Slack, one of the more exciting recent developments slowly establishing itself in mainstream drug development is atomic force microscopy (AFM). Developed as an add-on to enhance the scanning tunneling microscope, AFM adds an atomically sharp tip.
“By monitoring the surface of biological specimens with the sensitive tip, one can actually see the cellular membranes and even their subcellular components at high resolution. Ultimately, these and other emerging technologies are providing more physiologically relevant models.”