High-Throughput Screening

There are several decisions to be made when setting up an HTS laboratory, but the most important one is investing in the right equipment. Lynn Rasmussen, supervisor at the High-Throughput Screening Center in Southern Research Institute, a nonprofit drug discovery facility located in Birmingham, Alabama, screens approximately 3 million compounds a year. According to her, the most important question to ask is, what kind of throughput do you desire?

“There is a difference between screening 100,000 compounds a year and 30 million compounds, and the types of equipment you select will depend on the scale you intend to operate at,” says Rasmussen. While large, integrated systems are often adopted by bigger labs with high throughput, smaller laboratories have to be more conscious of cost, space and their throughput needs before making an investment. “I recommend modular systems for smaller laboratories, where you bring in pieces of equipment that meet your current needs and then bring in additional units as your needs expand,” says Rasmussen. “Adding pieces of equipment to match your throughput needs and standardizing to a few specific types of instruments help with managing a smaller lab.

Rasmussen has successfully used that approach in her laboratory when integrating additional liquid handlers, dispensers and microplate handlers into the pipeline as the lab’s needs have grown. Having multiple pieces of equipment performing the same function is especially helpful when equipment malfunctions. “In that case your throughput drops, but never to zero,” Rasmussen says. Integration of machinery from different vendors has also become less of a problem now that better informatics cross-talk and standardization of protocols and product specifications have been set across the industry.

“One of the most important things to consider in the current landscape is flexibility,” says Kiara Williams, product manager for Automation Liquid Handling at Thermo Fisher Scientific. “You want to buy equipment that will give you the flexibility to adapt to processes that may change, to add on accessories for added function, to work with different volume ranges and microplate formats; it should provide options to maintain accuracy and precision and should be scalable.” She advises that lab managers carefully review what their goals are for automating a process and then buy equipment that will meet those goals.

Laboratories can also drive down costs by reducing the cost per assay. Migrating from 384 to 1536 and now to 3456 well plates significantly reduces assay costs by reducing the amount of sample and reagents used. While screening in 3456 well plates is still quite challenging due to the low volumes and surface area involved, screening in 1536 well plates seems to have become fairly routine. “The recent advances in liquid handling technologies for accurate transfer of low [nanoliter] volume have made screening in 1536 well plates a much more realistic screening platform,” says Rasmussen.

“Choice of liquid handlers depends on the type of assay and can vary depending on the volume range, well plate format and density,” says Joby Jenkins, product manager at TTP LabTech. For instance, the Mosquito automated liquid handler developed by TTP LabTech can be used for dispensing 25 nL to 1.2 μL in 96 to 1536 well plates. The dead volume or the volume that the liquid handler can access from the source plate is another factor that often needs to be considered. “These days a big driver for compound managers and screeners is to be able to conserve the sample, and being able to access nearly all of that is very important,” says Jenkins. Liquid handlers can also work in conjunction with bulk dispensers to carry out low-volume pipetting steps as well as high-volume bulk additions, which allows one to mix and match pipetting steps within a single plate.

With HTS labs, costs can be driven down by investing in instruments that are reliable and adopting protocols that eliminate cross-contamination, false positives and false negatives.

Liquid handlers play a key role in eliminating cross-contamination between samples and assay runs. Nature of the pipetting motion to reduce air gaps, choice of fixed versus disposable tips, ability to handle a wide range of viscosities and surface tension of liquids are all factors that affect the performance and ultimately the success of the screen.

While keeping a close eye on the improvements in technology to help drive costs down is certainly important, performing in the most costefficient manner with what you have cannot be overlooked. “Always buy in bulk and negotiate with your vendors and suppliers,” says Rasmussen. It is sometimes advantageous to work with the same vendor for buying the various components and the consumables because it saves time, cost and effort when buying and troubleshooting. However, working with different vendors can also provide cost savings and better customization. “I would definitely encourage customers to try to find equipment that best meets their needs,” says Williams. “Having an open mind, shopping around and working closely with your vendors are definitely very helpful.”

Tanuja Koppal, PhD, is a freelance science writer and consultant based in Randolph, N.J.

Beckman Coulter
Four new cartridges for the PARADIGM detection platform include two luminescence detection cartridges optimized for 96- and 384-well plate formats, a new detection cartridge for BRET2* live cell assays and a Rhodamine fluorescence cartridge for a selection of cyanine dyes. The two luminescence detection cartridges complement the existing cartridge optimized for the 1536-well plate format. The well-isolating design of each cartridge is optimized for a specific plate format to provide increased sensitivity with reduced cross talk. The Dual Luminescence Detection Cartridge, optimized for use with BRET2 live cell assays, includes predefined protocols and data analysis tools and is ideal for the study of protein-protein interactions. The Fluorescence Intensity Detection Cartridge delivers speed and high sensitivity in applications using Cy3 and equivalent Rhodamine fluorescent labels.
www.beckmancoulter.com

Biofocus DPI
A new approach to discovery biology called ‘Intelligent Screening’ focuses on combining the know-how of the company’s scientists with its high-throughput and information-rich screening capabilities to generate faster results and accelerate partners’ drug discovery programs. In shaping its Intelligent Screening approach, BioFocus DPI calls upon: PrimePath™, its compound screening service that uses diseaserelevant complex assays in human primary cells; its high-throughput and information-rich ion channel screening capabilities; and its natural product screening platform, which is ideal for addressing difficult targets, such as protein-protein interactions. These services are complemented by BioFocus DPI’s worldclass screening libraries.
www.biofocusdpi.com

Thermo Fisher Scientific
The Multidrop® Combi nL bulk reagent dispenser for nanoliter-to-microliter volumes provides accurate, consistent, high-throughput dispensing for all laboratories across a volume range of 50 nL to 50 μL. The dispenser is easy to maintain and can be used to dispense all common reagents, diluents, buffers and solvents as well as viscose solutions, cells and beads, making it ideal for the large variety of assays and protocols. It uses a pressurized reagent container with valves to provide high precision and accurate control of liquid flow at all volumes. As a result, reagent waste is greatly decreased, minimizing costs and maximizing the utilization of precious samples. The intuitive graphical user interface makes all functions easy to set-up and use. The PC software control option enables greater flexibility, functionality and easier protocol creation.
www.thermo.com/multidrop

TTP Labtech
A new add-on bulk dispenser module launched for the mosquito™ nanoliter pipettor provides bulk reagent dispensing from eight independent channels to offer assay miniaturization through precise pipetting of compounds in up to 384-well microplates. With its disposable, positive displacement pipettes that ensure zero cross-contamination and low dead volumes, the bulk dispenser transforms the capabilities of the mosquito’s nanolitre liquid handling into a highly flexible system for high throughput screening laboratories. The new bulk dispense head attaches directly to the pipetting head and dispenses liquid from a flask/tube/bottle to part, or whole plates on the mosquito plate deck. Each ‘channel’ is supplied with an independent tube so different liquids can be supplied to specific rows of a given plate.
www.ttplabtech.com

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