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Guest commentary: Solutions to the drug development cycle and antibiotic resistance problems
January 2015
by Magnus Jansson, SymCel Sverige  |  Email the author
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The cell-based assay arena has become highly prevalent due to the serious, major and mounting medical challenges facing healthcare internationally—both financial in the field of drug development and curative in the arena of antibiotic resistance. Calorimetry is a mature technique, available in a modern 3D holistic format, that provides the answers to a number of some of these critical challenges.
 
Measurement of the total metabolic response of a biological system is a true time- and cost-efficient complement to existing assays and a highly valuable proposition.
 
Power and metabolic activity
 
All living cells produce heat through chemical and physical processes. By monitoring heat flow over time (J/s or W), significant information is obtained regarding biological systems. Calorimetry-based assays represent true measurements of the cellular phenotypic response. Any changes in nutrient status, the environment or external stimuli are reflected in the metabolic status of the living cell, which is directly monitored by the calorimetric assay. Isothermal microcalorimetry (IMC) is specific due to the fact that samples are kept at a constant temperature during the course of experiments.
 
Calorimetry: A specific footprint of cellular events
 
IMC provides the potential for rapid identification and quantification as it measures the total metabolic status and response of a cellular system. This makes IMC a true phenotype assay with the benefit that very little information is required about the system to be studied. Faster results in drug discovery and cell research are generated due to the fact that there is no need to know the pathways or receptors involved in a process. Consequently, novel systems can be studied directly, leading to quicker results in drug discovery and cell research.
 
IMC is a continuous measurement and the power over time curve is comparable to a specific footprint for the cellular events involved. For example, the power curves are different for necrosis and apoptosis, and the effects of different compounds can thus be classified based on the “kinetic” profile of a specific compound. For prokaryotes, there are different growth patterns for different species and for different nutritional status. This can potentially be used for rapid identification and quantification.
 
3D potential: Holistic approaches and a new dawn for drug discovery
 
Genotype-based research, complemented with phenotype results, is an important research direction in drug discovery that is replacing the previous focus on target-based drug development. Target-based research, with its large investments and reliance on different ‘omics, has shown limited output, with the number of new chemical entities significantly decreased.
 
Calorimetry, and especially IMC, has some unique properties that link high-throughput screening and primary screens to in-vivo results. IMC, being a continuous and nondestructive technology, allows the study of disease models from 2D to 3D to tissue, paving the way for cost efficiency and better predictability in drug development.
 
Novel cell-based assays with better predictive power link target binding potential to the true phenotype response of the organism, the human. Calorimetry is unique in that it is completely independent of cell morphology and media composition.
 
Most cell-based assays are limited to specific growth media or 2D cell cultures Calorimetry assays can be run using conventional 2D cell growth and various types of 3D cell models on matrices or synthetic tissue models, as well as tissue samples directly from donors. IMC increases the value of the assays, as it is not necessary to know the timeframe for a cellular event. Additionally, postexperimental analysis of protein and RNA levels can be performed.
 
These properties make IMC extremely relevant for studying disease models from 2D to 3D to tissue. Furthermore, it is also possible to apply whole-body calorimetry to correlate between in-vitro models and in-vivo results, especially in metabolic research, where energy expenditure is key.
 
IMC: An open platform that changes scientific development
 
Open platform solutions face strong demand, especially at the higher end of the assay market. Expensive lab equipment, usable for more than one assay type, presents a better and more cost-effective use of scarce resources than existing, highly specialized, locked-in equipment. IMC is a very open platform and its sole limitation is the creativity of the scientist, not the technology. The development of novel antibiotic substances is a prime example, in which IMC can easily be adapted for novel compound testing. The same IMC can then be utilized to evaluate cellular toxicity for lead compounds on mammalian cell cultures.
 
Applications: Metabolic drug discovery
 
Energy expenditure assays are used in metabolic disease drug discovery, but they are not limited to this field. It is clear that IMC has direct advantages for metabolic drug development since the kinetic profiling of the cellular metabolism makes it possible to distinguish between different cellular events. IMC is also well suited for finding and distinguishing between apoptotic and necrotic mechanisms and grouping antibody behavior-based killing kinetics and efficacy.
 
Antibiotic resistance
 
The medical/pharmaceutical world is facing an enormous challenge to rapidly develop novel antibiotic classes. IMC can easily be used to quantify the effects of novel antibiotics on bacterial viability and growth. Closed-ampule IMC captures basic pharmacologic information, e.g., minimum inhibitory concentration of an antibiotic needed to stop growth of a given organism. Also, it can simultaneously provide dynamic growth parameters—lag time and maximum growth rate. IMC provides a rapid, cost-efficient development scheme for novel antibiotics.
 
Antiparasite drugs
 
With IMC, it is possible to use whole intact organisms, thereby providing a novel tool for antiparasite drug development. Parasites of the Helmint type easily fit in modern, high-throughput IMC, and the drug efficacy can be tested on the whole organism. Manual input is minimal compared to the current microscopy assays used.
 
Bacteriological disease control
 
IMC can be used as a diagnostics tool in the field of bacteriological disease control. This is because IMC has very high sensitivity to rapidly detect slow-growing organisms, such as in tuberculosis, generating considerable time and cost savings. In the future, when personalized medicine has matured, IMC will potentially be used in prescreening for the treatment of diseases like leukemia. The direct drug effect can be studied in individual patient material prior to treatment with minimal lag, increasing the likelihood of a successful treatment scheme.
 
Ease of working with IMC
 
Novel technological developments now make IMC more adaptable to cell biology research. The combined benefits of increased throughput; presterilized, cell growth-compatible disposables; higher sensitivity; and decreased use of cells and chemicals, combined with easier data interpretation, are too important to disregard. Together with outstanding cost efficiency, this positions IMC as a state-of-the-art technology and increases the IMC-based assay usage in cell biology research.
 
Conclusion
 
Isothermal microcalorimetry-based cell assays provide multiple advantages, especially given that all living cells produce metabolic heat. There is a now great deal of valuable information available in heat which previously wasn’t given much weight due to old perceptions and a complete lack of tools.
 
IMC is a label-free technology that is sensitive, fast and low-cost, continuously provides important time-resolved data, is nondestructive, has few limits in morphology other than size and is nonspecific.
 
Furthermore, by carefully designing and posing the right questions in each study, IMC is no different than any other type of assay.
 
In conclusion, isothermal calorimetry complements a wide number of cell-based assays, from manual microscopic inspection to oxygen consumption and capacitance measurements. The only limit to possible application areas is creativity. Recent advances in equipment make calorimetry more accessible for the cell environmentalist. The holistic approach, in which 3D cultures and phenotype response are poised to provide predictable models, requires novel tools.
 
Calorimetry should now be thought of as label-free cell monitoring. Essentially, calorimetry is a good complement to the many current trends in drug discovery and prioritized research areas. Indeed, cell-based assays can now be performed on a versatile and adaptable platform that provides considerably more information with significantly less effort. Calorimetry has arrived.

Magnus Jansson is chief scientific officer of SymCel Sverige AB
 
References
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  2. Kirchhofer, C.; Vargas, M. Acta Trop. 2011 Apr, 118(1), 56‒62; doi: 10.1016/j.actatropica.2011.02.003; Epub 2011 Feb 21.
  3. Global tuberculosis report 2013. WHO Library Cataloguing-in-Publication Data: 1. Tuberculosis—epidemiology. 2. Tuberculosis, Pulmonary—prevention and control. 3. Tuberculosis—economics. 4. Tuberculosis, Multidrug-Resistant. 5. Annual reports. I. World Health Organization. ISBN 978 92 4 156465 6.
  4. Howell, M.; Wirz, D. et al. J. Clin. Microbiol. 2012 Jan, 50(1):16‒20; doi: 10.1128/JCM.05556-11; Epub 2011 Nov 16.
  5. http://en.wikipedia.org/wiki/Isothermal_microcalorimetry.
  6. Braissant, O.; Wirz, D. et al. Sensors (Basel) 2010, 10(10), 9369‒83; doi: 10.3390/s101009369; Epub 2010 Oct 18.
 

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