Modern drug discovery is based predominantly on parameter research. Individual factors like gene expression levels, protein levels, protein activity and localization are measured and extrapolated into in vivo function for treatment in humans. The measurement of factors and levels is limited in time and space and to a large extent performed in synthetic cell models based on the two-dimensional growth of immortalized cell lines – far away from the tissue/organ/whole organism that will eventually be treated, usually for an extended period.
The proposal is to try and increase the knowledge of cell-response upon treatment and to reduce the gap between synthetic assay conditions and real live whole human response. The way to do this is to introduce the phenotypic assay where the total response of all the mechanisms of life is accounted for. The extrapolation of the effect in a two-dimensional (2D) cell culture to the in vivo human situation has time and again displayed less favorable outcomes.
There are numerous examples where clinical trials have been unsuccessful due to limited efficacy or toxicological side effects. One simple example is the screening of anti-cancer drugs performed in oxygen rich 2D cell culture in which very high specific metabolism gives very different chemical hits compared to the screening on hypoxic 3D cell cultures. The oxygen-starved situation will be a closer match to the situation in solid tumors in vivo. Performing a metabolism based screening with phenotype based readout will provide a possibility to screen closer to the real-life situation.
Since the calScreener calorimetry based assay provides a direct measurement of the cell activity without any labels or additions of any kind, it is not measured via a proxy measurement; it is a direct measurement of the energy release. The unique upside is that it is not parameter testing. There are no other label-free and non-destructive technologies available that can be used to study the net effect of all cellular parameters at once and in the correct context, regardless of sample composition and morphology.
The calScreener is an accurate phenotype (functional) assay as compared to most other technologies that use parameter based (genotype) testing. Most assays are also predominantly end-point assays, where samples are gathered at one or a limited number of time points, in contrast to the continuous kinetic measurement of the calScreener.
Direct Metabolic Readout (DMR) provided by the calScreener gives the scientist access to an unbiased assay where the effects of treatment are studied in a correct biological context resulting in greater predictive value for cost-effective and rapid drug development.
To bridge the gap between screening on isolated components to 2D cell cultures to 3D tissue to the in vivo human situation – increasing the predictive power of the scientific hypothesis in drug development
The possibility to direct continuous measurement of effects in hard or previously impossible to monitor environments like 3D cell cultures or bacterial infections in complex matrices
The extension of 3D based drug discovery would be to apply the same assay principle on actual patient tissue samples to evaluate the best possible treatment based on the real patient response.
Magnus Jansson, CSO, Symcel commented: “At SymCel, we predict that the recent developments in calorimetric equipment – enabling small volume samples and multichannel equipment adapted to microbiological laboratory settings – will lead the way to new 3D assay tools in the development of novel oncology treatments. This technology will also serve as a tool for in vitro diagnostics and personalized medicine.”
