In drug discovery, pharmaceutical scientists often use high-throughput screening (HTS) to identify candidates for new medicines. To get the most from the assays, companies frequently automate some of the steps. But automated HTS is used in more than pharmaceutical studies, and the applications keep expanding.
For now, big pharmaceutical companies buy and use much of the equipment sold for automated HTS. Larger biotechnology companies that specialize in biotherapeutics also use considerable HTS automation. Also, contract research organizations (CROs), like Charles River, automate some HTS processes. Even some universities set up automated HTS.
When asked about the major components of an automated HTS platform, Kevin Moore, head of markets and applications at Tecan, says that a key part is liquid handling. He should know after running HTS at Merck in the U.K. and 12 years at Tecan. Moore also notes the detection component. “At some point, you need some sort of readout,” he says, and that could be something like Tecan’s Spark multimode microplate reader or mass spectrometry. Other items can include robotic arms, centrifuges, sealers, shakers, stirrers, and so on.
In thinking about a complete automated-HTS system, Moore says, “It often takes up a couple meters or more, needs dedicated people to operate it, and software ties it all together.”
Building a system
Depending on specific needs, scientists could build an automated HTS system in various ways. “Normally, people go to integrators, like us,” Moore explains. “Tecan has parts of the process in place, and we buy other pieces to make the system.”
As an example, Moore says, “You could buy our Fluent liquid handler and make an HTS system from it.” He adds, “It’s capacity and speed let us put in all of the peripherals and integrate the devices.”
Assembling the right system, though, is not an easy task. “Lots of research is done by customers before they even start talking to companies,” Moore explains. The customers do research online or go to a trade show to get an idea of what they want. “Then, the customers talk with a salesperson, and we can do demos,” he says.
In the shopping phase, many customers want more than promises. “More and more customers need some sort of data,” Moore says. “They need to see examples of what a system can do.”
The Tecan integration group (Labwerx), can do one-off builds. “They help a customer formulate the idea into something deliverable,” Moore explains. “Then, this team goes out to run the unit until it meets the customer’s expectations.”
Fit for purpose
At Genea Biocells, scientists use automated HTS for cell-based screens focused on developing therapeutics for orphan neuromuscular diseases. As explained by operations director Charles Martin, “Our pipeline is driven by a scalable, proprietary human pluripotent stem-cell platform.” When asked about the technical challenges of applying automated HTS at Genea Biocells, Martin says, “Our assays depend on multiple parameters, one of them being cell density. We have to control and eliminate wells that do not meet specific seeding criteria, depending on the assay.” As he adds, “It is worth noting that the HTS Tecan platform was instrumental in helping Genea Biocells to win an orphan-drug designation for GBC0905, the first in class therapeutic agent to treat facioscapulohumeral dystrophy.
Charles River runs automated HTS with fully automated laboratory workcells and as standalone small-scale automation. “The fully automated workcells are suited for undertaking relatively straightforward biochemical assays, where reagent stability or availability is not an issue, and it allows increased plates per day,” says David Cronk—director of high throughput screening sciences at Charles River. “We also widely deploy full automation within our compound-management facility to support preparation of screening plates at all stages of the HTS workflow.” Scientists at Charles River also use smaller methods of automation to transfer plates between readers or liquid-handling stations. “This allows us to adopt a highly flexible workflow to accommodate a diverse range of projects,” Cronk explains.
When asked about the key technical challenges in automating HTS, Cronk points out complexity. “Systems have traditionally required dedicated super-users, which limits the flexibility of multiple users to be able to step up and use the platforms as required,” he says. “This, coupled with overall system reliability—specifically because systems frequently change—has been a limitation.”
In all cases, HTS must be reliable. “Automation that faces reliability challenges proves more of a hindrance than a help,” Cronk says. “This is particularly true when reagents are supplied by our collaborators and may be of limited supply.”
The most recent additions of automated HTS at Charles River consist of platforms added to its compound-management technology. Cronk says that these platforms “increase the capacity for cherry picking of samples at volumes higher than can be efficiently handled using acoustic dispensing technology.” He adds, “The system has been designed to undertake all aspects of the process from plate centrifugation through final plate delivery.”
Shrinking systems
When asked about some of the key trends in automating HTS, Moore mentions miniaturization. For example, he notes systems working with 384- or 1,536-well plates. “Tecan has had these capabilities for some time now both in terms of liquid handling and detection,” he says.
By using smaller wells, an HTS system requires less reagent, and that saves money. Such automated HTS systems require a liquid handler that can dispense very small volumes.
On the other hand, as scientists rely more on the phenotypic assays and move toward ex vivo disease models, the demand for relevant cell-based assays increases exponentially. “So, some companies are moving HTS to include sources like stem cells, primary cells, or cells in general,” Moore says. With cell-based methods applied to HTS, the automation can provide large amounts of data that pave the way toward the identification of new medicines and treatments.
The kind of automated HTS that makes sense depends on many factors. Also, the purchase process requires thorough research, including finding a vendor that will work alongside the customer to ensure that a platform performs as needed.