The Impact of Calorimetry Based 3D Phenotype Assays

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The Impact of Calorimetry Based 3D Phenotype Assays

Magnus Jansson, PhD, Chief Scientific Officer, SymCel Sverige AB

A necessity for drug discovery and personalised medicine

Modern drug discovery is based predominantly on parameter research. Individual factors such as gene expression levels, protein levels, protein activity and localisation 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 immortalised 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 to 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 favourable outcomes. There are numerous examples when clinical trials have been unsuccessful because of limited efficacy or toxicological side-effects.

One simple example is the screening of anticancer drugs performed in oxygen-rich 2D cell culture in which very high specific metabolism gives very different chemical hits compared with the screening on hypoxic 3D cell cultures. The oxygen-starved situation will be a closer match to the situation in solid tumours 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 with most other technologies that use parameter based (genotype) testing. Most assays are also predominantly end-point assays, in which 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 wherein the effects of treatment are studied in a correct biological context, resulting in greater predictive value for cost-effective and rapid drug development:

  • the ability 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 such as 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.

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 personalised medicine.