Assays
Figure 4: Distribution of cell-based and biochemical assays with respect to development time
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0 1 2 3 4 5 6 7 8 9
Higher Percent Biochemical Assays Higher Percent Cell-Based Assays
1 2 3 4 5 6 7 8 9 12 Assay Development Time in Months
© HighTech Business Decisions
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and cell-based assays are notoriously more com- plex than biochemical assays. The HTS 2010 study respondents can be divided into two groups: labs that perform a higher percentage of biochemical assays (17 labs) and labs that perform a higher per- centage of cell-based assays (29 labs). The distri- bution of each of the two groups, with respect to their assay development time, is illustrated in Figure 4, and reveals that labs using predominant- ly biochemical assays have shorter development times, an average of 4.1 months, whereas labs using more cell-based assays have longer develop- ment times, an average of 6.2 months. Further, the 10% of directors who reported increasing assay development times in the past few years also report increasing their percentage use of cell-based assays.
Solutions for improvement
Several directors commented below that the biolo- gy in the assays can be surprisingly complex.
“We think of single molecular targets, but often that is not really how things work, so you don’t get what you expect.”
HTS laboratory
“Physiological relevance is our greatest assay devel- opment roadblock. We spend a lot of time convinc- ing teams to do a screen in the most physiological rel- evant system. We have the most difficulty with the translation of our in vitro results to in vivo systems.” HTS laboratory
Interestingly, several directors said communication with the scientists bringing the assay into HTS is a challenge. These directors, who are mostly at core aca- demic screening centres, are providing service to their university communities, and as such, do not partici- pate as early in assay development as directors at more integrated companies. One of these academic centre directors describes the benefits of early collaboration.
“For us, one of the things is communicating to the investigator the ways in which HTS is different from a bench top experiment. Controlling for tem- perature is more challenging and so is the time needed to initiate and read the assay. With our automation, we do things in batches and we can’t just read the results whenever we want to.” Non-commercial laboratory
More time needed for cell-based assays Assay complexity contributes to development time
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Innovative tools and enhancements to current tech- nology will positively impact assay development. Already, HCS and patch clamp instruments are more robust with faster throughput, and label-free technology has opened up opportunities for intractable targets. One HTS director described the contribution of innovations in technology.
“More complex assays are needed now to find hits. HCS is probably the most important. Now we can do phenotype assays in high throughput. We are no longer limited to doing follow-up assays on hits from biochemical assays. We can screen targets directly in a smart, multiplexed way. Population patch clamp technology is also important and mass spectrometry (MS) is coming to HTS. With our UPLC device, we can screen 10,000 data points in a week. With two instruments in tandem, we can screen our complete library of 250,000 compounds in six weeks, which makes it competitive.”
HTS laboratory
Increased availability of commercial reagents and further outsourcing of reagent production will also benefit assay development. Currently, 35% of HTS labs outsource cell line development or pro- tein production according to the HTS 2010 study. In addition to outsourcing reagent production, a few of the HTS directors currently outsource some custom assay development. The comments below reveal some of the motivation for outsourcing.
“We prefer to outsource protein production, cell line development and scale up. We outsource items that we don’t have enough infrastructure for and requires no innovation on our part.”
HTS laboratory Drug Discovery World Summer 2010
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