Genomics


assays to assess cardiotoxicity. Research aimed at characterising stem cells and identifying the sig- nals and stimuli that trigger and direct their growth, differentiation and death, will accelerate progress in developing stem-cell derived cell lines for research, preclinical studies and high through- put screening (HTS), and for advancing cell-based strategies to repair and replace damaged or dis- eased tissues and organs.


Embracing the complexity of the cell DNA is often described as the fundamental build- ing block of life, but while it is an essential com- ponent of any unicellular organism or cell, a strand of DNA cannot on its own multiply or carry out the instructions for life encoded in its chemical sub- units. The basic unit of life, therefore, is the cell. It embodies the DNA and ensures that its messages are transcribed and translated. Understanding those functions and characterising them at the molecular level will open new doors for drug dis- covery, leading to novel drug targets and therapeu- tic strategies, safer drugs with less chance for adverse side-effects and late-stage clinical failure due to toxicity, and more targeted treatments with well-defined mechanisms of action that will usher in an era of personalised medicine.


The biopharmaceutical industry continues to be plagued by the failure, during large-scale clinical testing or even withdrawal post-marketing, of promising new drugs due to toxic effects, despite extensive preclinical studies and successful Phase I and II clinical trials. The economic toll of these failures is enormous. The loss may surpass $1 bil- lion for a compound that was discovered in an HTS campaign, developed through an intensive optimisation workflow and subject to an array of preclinical analyses and extensive early-stage clini- cal scrutiny. Importantly, new and potentially life-saving drugs are being put on the shelf despite years of development and investment (that could have been spent on other promising candidates), because their toxicity could not be anticipated and avoided. Human cell-based models that simulate drug and metabolite processing and their effects in the body offer a promising solution to supplement or replace traditional animal studies and assays currently used for preclinical ADME-tox and pharmacoki- netic/pharmacodynamic (PK/PD) testing. Embracing the complexity of the cell means understanding its intricate signalling networks and integrated biochemical pathways, compre- hending the full range of cell behaviours and appreciating the role a cell plays within a tissue or


Drug Discovery World Spring 2013


organism depending on its type, location and environmental cues; then using this knowledge to gain value from a cell-based application, whether in the form of a live-cell assay for high content screening, a cell-based model for ADME-tox test- ing, or a cell therapy to treat disease. All of these are realistic and valuable goals that can be achieved by applying advanced technologies and methods for growing, processing, imaging and analysing cells and by furthering the industrialisa- tion and standardisation of cell production for therapeutic applications.


The era of live cell imaging


Innovative high-speed, high-resolution imaging technologies that include super-resolution microscopy and a host of related techniques will dramatically enhance the ability of scientists to study cell structure and behaviour at the molecu- lar level. Some super-resolution microscopy tech- nologies, which can achieve 100-80nm spatial res- olution, are now enabling live cell imaging and opening a window into the mechanistic workings of intracellular processes. This, in turn is helping enable discoveries and insights not previously pos- sible. The combination of nanometer-scale resolu- tion, high speed signal detection (so that ‘real- time’ imaging means capturing cellular and sub- cellular processes as they are occurring), and the capability to record, store and analyse the large amounts of data generated is yielding a wealth of new knowledge.


19


GE Healthcare Cytiva™ human stem cell-derived cardiomyocytes. Inset images from HCA cardiotoxicity assay show cells exposed to increasing concentrations of an anti-cancer drug showing disruption to mitochondrial integrity (red) and calcium homeostasis (green)


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