Screening


more relevant, and a more accurate reflection of the target biology.”


von Leoprechting agrees: “Label-free detection greatly expands the types of cells that can be used, including human primary cells and stem cells, as well as the types of targets that can be studied. Since the cells are not genetically manipulated to intro- duce a label, label-free methods allow the researcher to measure the response in a manner as close to the authentic cell physiology activity as possible.” “Kinetic profiles can be obtained that are quan- tifiable and lead to information suitable for appli- cations such as cell culture QC, proliferation, cyto- toxicity, receptor studies and cell invasion/migra- tion to name a few,” adds Hurwitz.


Biochemical interactions also benefit from label- free analysis “showing the interaction as it happens in contradiction to an end-point assay”, says Burtsoff Asp. “The label-free interaction data pro- vides not only information such as kinetics, affini- ty, thermodynamics, specificity, concentration and enzyme kinetics, but can also be used for data quality control or trouble shooting supporting con- fident decisions in research.”


“Fragment-based lead generation is becoming an increasingly important component of drug discov- ery,” says Silva. “The Octet® platform’s sensitivity and ability to assay precipitating compounds using a ‘dip and read’ format, its greater dynamic range and our new analysis software capabilities, enable rapid screening of fragment libraries in a microplate format.”


“Label-free assays also provide great opportunity in delivering simplified methods for studying the complexity of biological pathways,” says Gallant. “The universal assay format allows one to study multiple pathways at once, making assay develop- ment less tedious and data more easily comparable.” We expect to see “greater adoption of label-free in non pharma/biotech areas through greater accessibility due to decreased cost, decreased instrument size and higher value for money capi- tal”, says von Leoprechting. “This may also assist the pharmaceutical industry in widening the out- sourcing and collaboration potential with academ- ic partners and CROs.”


Continuing challenges


“Label-free technology is still early in its growth phase, especially for cell-based assays. How it can be used and integrated into standard procedures offers the greatest possibilities. Deconvolution of the high content data has been one featured chal- lenge and is one that both industry and customer have been working together to improve,” says


Drug Discovery World Winter 2010/11


Hurwitz. “There is continuous work going on to further develop system performance and also to improve support for data handling and data inter- pretation,” adds Burtsoff Asp.


One of the challenges limiting the use of label- free technology is that the experimental results are perceived to be a black box. The technology is per- ceived to give an observable result that is only cir- cumstantially connected to a biological event. While this perception is more relevant to cell-based experiments, it colours researchers’ interest in label-free technology in general.


Gallant comments: “Moving to label-free assays from labelled assays requires adopting a new approach – a change in the mindset of how drug discovery gets done. Scientists are accustomed to the use of labelled assays where the labelled reagent or reaction occurs due to one specific effect in one specific pathway. The change to label-free assays requires moving away from low informa- tion HT assays to an assay type of moderate throughput with more informative, yet more com- plex, data output than that of binary assay data of typical HTS assays.


“Our main strategy to overcome the perception that label-free assays are ‘black box’ has been to focus on education about the approach and its ben- efits,” says Gallant. “We sponsor talks at shows, perform tutorials and webinars to educate people about the power of label-free, and we have gener- ated a strong set of data using modulators of dif- ferent parts of the signalling pathways, showing how pathways are specifically blocked or upregu- lated; proving the connection of the receptor acti- vation to the cytoskeletal rearrangement leading ultimately to the change in impedance.” In addition, Hurwitz says: “Application notes, sponsored tutorials, and webinars driven by user success stories provide the best examples of how the perceived ‘black box’ data is translated into mean- ingful results. An increase in peer reviewed publica- tions also supports the technology’s true value and discoveries that previously were unattainable.” von Leoprechting comments: “We work with leading researchers who are successfully using label-free technologies such as the EPIC system in their mix of tools and workflows in modern drug discovery, and enable a wider range of researchers to use and validate label-free alongside other labelled technologies on a cost-effective multi- modality plate reader platform.” There are clear examples of the complementary and correlated nature of label-free approaches to single target measurements. We are able to demonstrate that label-free traces “give clear information on more


47


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80