High Throughput Screening Automation: An Introduction for Laboratory Scientists

In the world of scientific research, particularly within drug discovery, efficiency is paramount—this is especially true of High Throughput Screening (HTS). My own scientific journey transitioned from labor-intensive manual assays to exploring and embracing automated technologies that expand the potential for novel discoveries. Let's explore the landscape of HTS.

Fundamentals of High Throughput Screening

Those of us seeking automation in HTS are driven by goals beyond speed. We strive to miniaturize assays, enhance data collection volumes, and integrate redundancy within instruments to ensure reliability and continuous operation. You’ll need to manage a vast array of plates and consumables, each requiring strategic storage solutions, data handling, and variability in how they’re processed (like selecting the appropriate downstream assay based on upstream data, for example).?

However much I appreciate liquid handlers, they often need to be supplemented with other equipment in order for HTS to be more efficient. The transition from traditional tip-based liquid handlers to non-contact dispensers marked a significant milestone in how I think about enhancing efficiency – thanks to my experience working for High Res Bio, an integrator of large HTS systems (and much more). Tip based liquid handlers have their place in HTS in almost every case, but it’s wise to consider non-contact dispensers as well for the time and cost savings.

The evolution of HTS includes a recent shift towards more intricate, longer-running cellular assays using valuable cells, necessitating rigorous sterility and aseptic techniques – workflows performed by “streaming” in new assay plates instead of setting up “batches” of plates periodically – all within a clean, enclosed environment.

Selecting appropriate instrumentation is a critical strategic decision, encompassing a range of tools from liquid handlers to multimodal readers, washers and dispensers. For example, the integration with cell culture maintenance systems may be crucial, as these systems supply the fresh cells vital for subsequent HTS applications. I’ve helped dozens of clients make difficult decisions about which equipment to choose, balancing cost with capability, flexibility, and reliability – and there’s rarely the “best choice” but rather choices ranked by your priorities and tolerance for certain constraints.

Central Concerns in HTS (and a Concern to be Concerned About)

Maximizing throughput remains a top priority, alongside ensuring assay uniformity, robust storage solutions, redundancy and reliability (ensuring uptime), and the ability to run multiple assays concurrently. As we navigate these priorities, we also focus on future-proofing our labs. This means selecting systems and instrumentation that can adapt to the evolving demands of scientific research, balancing flexibility with cost and complexity—a strategic and visionary approach that deserves our focus here because it’s often used as a buzz-word and the pros/cons of such a feature are often misunderstood.?

Is “future-proof” a sales feature or a user feature? It depends. Sales features are aspects of a product that are highlighted to attract buyers and convince them of the product's worth. User features are aspects of a product that directly affect how users interact with the product and the value they derive from using it. Often, “Future-proof” can’t be measured or used directly – it’s basically the ability of a system to be reconfigured, adapted, or changed as your needs evolve. You can decide in which cases you think it’s a buzz-word or an actual useful benefit.?

The upsides to a system optimized to be future-proof are obvious, like dating two people at once, but the downsides are obvious too if you take a moment to consider them. We are still talking about automation, sorry. Let’s explore the downsides to optimizing for future-proofness.?

1. Higher Costs: Future-proof designs typically require advanced technology, leading to higher upfront costs.
2. Complexity: These systems are more complex, requiring specialized training and potentially leading to longer downtimes.
3. Overengineering: There's a risk of adding unnecessary features that inflate costs without enhancing current laboratory operations.
4. Implementation Delays: The design and setup of sophisticated systems can extend development timelines, delaying their operational use.
5. Uncertainty in Future Needs: Accurately predicting technological and laboratory advancements is challenging, risking obsolescence or suboptimal choices.
6. Resource Diversion: Significant investment in future-proof systems might divert funds from essential current needs or upgrades.
7. Maintenance and Support: Advanced systems may require costly and complex maintenance and can lead to vendor dependence for support.

Instead of throwing money, time, people, and complexity into a "future-proof system", initially it may be wise to focus on creating a specialized workcell or a set of instruments tailored to specific workflows, constrained by budget and simplicity. This strategy helps manage costs and complexities while laying a foundation for scalable automation. Your laboratory users will be more comfortable learning such a system, so it’ll be used more often in my experience. Once these automated workflows demonstrate success and a clear return on investment, we can naturally progress to expanding our setup or adding new assemblies for more ambitious applications.

This phased approach isn't just about resource allocation; it's about establishing a reliable automation foundation to support future scientific breakthroughs. By marrying precise management of current needs with proactive planning for future possibilities, we aim to cultivate a laboratory environment that excels in both precision and adaptability, paving the way for continuous innovation.

Running HTS systems effectively involves a delicate balance between automation and human oversight, ensuring that reagents are used efficiently and remain stable under various conditions, as well as troubleshooting quickly as challenges arise. The challenge of minimizing waste, whether it involves tips, plates, or valuable reagents, is a continual focus, guiding us toward more sustainable and economical laboratory practices. Costs can pile up very quickly and it can be hard to predict exactly what your operating costs will be if you haven’t built automated systems around HTS.

Workflows and Equipment Limitations and Bottlenecks

Reflecting on the range of workflows, from cellular reporter assays to sophisticated high-content imaging, highlights the diversity of tools required for effective HTS. Each phase, from cell seeding to compound addition via advanced dispensing methods, illustrates the intricate interplay of technological and scientific limitations. There are always limitations and bottlenecks and it’s our responsibility to predict and control how and where we choose to place those constraints. Decisions on techniques like centrifugation (like BlueCat Bio) versus traditional plate washing can impact overall workflow efficiency, and introduce limitations that you can learn by asking me or your colleagues.?

Just remember there are always bottlenecks and limitations in any process, and that’s especially true in our industry when you’re working with robotic and biological systems at the same time. You want to choose the bottleneck and maintain control and transparency so you can stay up and running. I’ll write more on this in a future post because it’s a huge topic that is universal in process engineering – too broad for this post.

Reflecting on HTS

Embarking on HTS necessitates addressing several critical questions, from assay types and throughput capabilities to the operational duration of screening processes. Every detail is crucial, including the management of lids and seals and ensuring that instruments are up-to-date and compatible with current lab workflows. If you want to explore every consideration, please reach out and I’ll help you uncover insights to improve your processes, equipment choice, and overall approach to a solution to HTS.

HTS plays a pivotal role in advancing the frontiers of scientific discovery, and is not merely about adopting new technologies; it is about fundamentally rethinking how we conduct scientific research.