Under New Management
High-throughput screening affects more than just the assays in the main development pipeline. Supportive tools and services can also be affected.
Meeting the demand for compounds for high-throughput screening is a challenge that requires some innovative, high- throughput solutions of its own. Mike Stock, group leader in compound management operations at Biofocus DPI (www.biofocus.com), talks about what it’s like to do compound management for the National Chemical Genomics Center (NCGC, part of the NIH), one of ten centers in the molecular library screening network.
At the beginning of the project, he says, there was just a small repository, and they were starting from scratch. It was an opportunity to customize the repository and the compound-management system needs from the ground up to service a high-throughput screening facility.
“We had to design and build a process without having end users to talk to,” adds Stock. The first user contact it had was with the NCGC and it was, therefore, heavily influential in the shape of the final system.
Among the most important considerations in compound management is the volume of compound solution to maintain and to aliquot for each screen. BioFocus settled on 45 uL of 10 mmol DMSO (dimethyl sulfoxide) solution per year.
Another factor was the storage of the tubes. BioFocus opted to use a system that uncaps and recaps, instead of a system with a septa that is penetrated by a needle. To counteract the effects of air on the solution, it handles the tubes in a nitrogen atmosphere, which has proven to be a uniquely successful strategy for compound management.
DMSO is hygroscopic, and each exposure to air results in water getting into the solution and possibly changing the solubility of the compound. “One of the things we did agree to, as part of the NIH collaboration, was to do an annual maintenance quality control check,” Stock points out. “This is where we do the statistical sampling of the compounds kept as solutions. We agreed to check them, and if they weren’t any good, we would get rid of them and start over. We have two year-old solutions that we’ve handled quite often and the QC is good. We haven’t had any stored DMSO solutions fail our maintenance QC.”
For comparison, many pharmaceutical companies have had no QC on their stored DMSO compounds, but some of them have found that degradation in stored compounds has resulted in problems with hit confirmation and follow-up within high-throughput screens. BioFocus is also piloting single-use plates to send to the screening facility upon request.
For many scientists, this is a thought paradigm shift, especially those who like to keep their compounds and other stored supplies close by for peace of mind; however, they are slowly coming to realize that for the sake of the integrity of the stored compounds it may be better to let go and let a specialized facility handle them.
On one hand, researchers will have to let go of older ways of doing things in order to make the fullest use of automated high-throughput tools; the benefits certainly outweigh the discomfort of making the change. On the other hand, the costs are not so easily dismissed.
Labs have dealt with this in various ways, such as sharing high-throughput resources like the NIH Screening Centers Network, or by teaming up with a larger company to share a piece of advanced equipment. Many labs are building their own prototypes and designing their own systems. It’s an exciting time to be getting started with high-throughput automation.