DRUG DISCOVERY - Benefits of Acoustic Liquid Handling in Drug Discovery

INTRODUCTION

The pressure isn’t easing to get more done in the laboratory, nor is the push to get results faster. Innovation remains steadfast with 53 FDA-approved novel drugs in 2023.¹ In 2022, 37 novel drugs were FDA approved, with 24 (65%) using an expedited pro­gram – underscoring the priority to bring life-saving treatments to market.²

Today’s drug discovery favors precision drug therapy, push­ing complex modalities like combination therapies and biologics, along with cell- and gene-based therapeutics to the forefront. Major advances in areas, such as synthetic biology, advanced dis­ease model creation, and integrated multi-omics-based work­flows, continue to evolve our understanding of human pathophysiologies and bring the hope of new treatments to the market with an ever-increasing speed. Aside from being intricate, they are also lengthy processes with greater risks for human error.

There are clear needs in the market for simple but robust so­lutions that streamline workflows, provide precision and accuracy, and provide a pathway to future workflow expansion as life sci­ences technologies evolve.

On the heels of the pandemic is an inevitable drop in drug discovery ROI that stands in contrast to the pandemic’s height.³ Though investments remain robust, so is the call to reduce costs.

Supply chain issues and inflation are further straining labo­ratories. The three-fold pressure of heightened complexity, accel­erating pace, and financial strain calls for a revolutionary, economical solution that enables labs to accelerate research ef­forts and minimize errors.

Automated acoustic liquid dispensing technology is a game changer – whether deployed as a stand-alone instrument, in a scaled-up workstation, or as part of fully integrated systems – when it comes to handling complexity in efficient and cost-effec­tive ways.

In a single primary screening campaign, labs can be re­quired to screen up to 1-3 million molecules to locate potential new medicines. Imagine manually transferring an astounding 500,000 samples each day! That’s how many samples can be run on an acoustic liquid handler.⁴

However, with burgeoning advances in protein-target rela­tionships, AI-enabled target-toxicity profiles, polypharmacology, and biomarker-based stratifications, early stage discovery efforts may need to instead profile fewer primary molecules, but test those candidates over a higher number of complex assays and target-agnostic workflows, such as high-throughput transcrip­tional profiling.

Acoustic technology is well-poised to accelerate research de­cisions for new and existing molecules.

TODAY’S CHALLENGES IN THE DRUG DISCOVERY PROCESS

With drug discovery science increasing in complexity, labs researching new therapies face several common challenges. The first is fixed annual budgets, despite continuously changing re­search priorities. Additionally, inflationary pressure impacts labor, cost of raw materials, and more – not to mention the cost of lab­oratory space in tech hubs. This makes it even more critical to en­sure no errors are made along the way – something to which tedious manual workflows are prone.

Labs also face time and resource limitations for staff, inde­pendent verification, and validation programs that require train­ing and re-training staff. The skilled labor shortage added to the high process standardization required for staff accreditations and certifications creates bottlenecks – particularly for highly manual laboratories.

Variability among human operators overseeing manual processes can complicate standardization, reproducibility, and accreditation. Daunting sample and data management can over­whelm lab staff who rely on manual processes. Laboratories also face the evolving complexity of balancing today’s liquid handling needs with tomorrow’s unknown demands.

All of these constraints detract from critical work but can be addressed through a trustworthy instrument scaled to laboratory needs while facilitating better data and sample management.

WHY AUTOMATE LIQUID HANDLING ACOUSTICALLY?

Automated acoustic liquid handling is a synergy of reliable, contact-free instrumentation paired with intuitive software that creates rapid reproducible success, especially beneficial in a race against time. In particular, miniaturized sample management and assay-ready plate creation benefit from the unparalleled accuracy and precision provided by acoustic dispensing.

Lengthy cycle times, physical space constraints, and lack of skilled labor hinder laboratories that rely on manual liquid dis­pensing, making reproducibility challenging and high-throughput screening (HTS) nearly impossible. Some liquid handlers demand repeated cumbersome calibrations be verified on every instru­ment transferring the reagent. These are limited in volume ranges and workable reagent types and, at best, approximate against inconsistent reagents.

Acoustic liquid handling, on the other hand, deploys sound energy to eject precisely sized droplets from a source onto a mi­croplate, slide, or other surface. Our instrument applies Acoustic Droplet Ejection (ADE) to accurately and rapidly transfer up to 700 drops of fluid per second.⁵ The acoustic liquid handler is in­herently capable of combinations of various sample types: capa­ble of providing 1-to-1, many-to-1, and 1-to-many, and many-to-many complex combinatorial transfers to either dry or prefilled wells.

The technology has become a mainstay in sample manage­ment, HTS, and assay development workflows. Acoustic dispens­ing is enabling previously unimaginable throughputs in advanced synthetic biology and genomic applications.

Acoustic liquid handlers apply Dynamic Fluid Analysis (DFA) for fluid transfers that simplify experimental setup and enable a higher degree of experimental and workflow flexibility. The instru­ments determine transfer parameters automatically at runtime for a specified fluid set, eliminating the need to adjust transfer parameters. They are versatile enough to work with complex reagents that can vary in fluid properties and are exceedingly accurate due to DFA’s ability to adjust the acoustic energy to changing fluid properties.

HOW ACOUSTIC LIQUID HANDLERS STREAMLINE LAB OPERATIONS

Acoustic liquid handling automation uses substantially fewer materials, reduc­ing laboratory costs through miniaturiza­tion and maximized HTS campaigns. It also minimizes human error and risk of handling toxic or hazardous materials.

Increased assay precision reduces replicate requirements, extending samples across a greater number of possible ex­periments. For example, direct dispensing of cherry-picked samples extends sample life, while acoustically diluting small mol­ecules and biologics generates vitally ac­curate and reliable concentration informa­tion.

With cell-based assays in demand, acoustic liquid handlers offer the ability to readily generate assay-ready plates for testing various samples. Assay-ready plates provide a convenient pause point to synchronize with cell cultures that are ready for plate seeding. Automated cell culture enables large amounts of multiple robust and reliable cell lines for assays, fa­cilitating timelier responses to simultane­ous requests from assay-development labs for screening or supply batches.

Acoustic liquid handling automation solutions also facilitate improved data and sample management as workflows be­come increasingly complex. With better sample traceability, the technology makes feasible identification of many targets through the biotech revolution and numer­ous combinatorial technologies for com­pound collection.

ACOUSTIC LIQUID HANDLING IN ACTION

Evotec, a drug discovery company in France, implemented acoustic liquid han­dling as part of an integrated system. “In 2020, we prepared around 27 million compounds with our Echo platforms to support the primary assay up to the profil­ing step,” said Marion Stodel, Research Scientist, Sample Management at Evotec.⁶

They achieved the sample manage­ment goals of maximizing inventory usage, introduced flexibility of collection assemblies, increased delivery efficiency of assay-ready plates in nano-volumes, and improved data management efforts.

“Echo is the heart of the platform and works with acoustic transfer technology,” Stodel continued. “It transfers compounds from compatible source plates to destina­tion plates. The smallest volume that can be transferred is 2.5 nanoliters. Dispens­ing such a small volume saves expensive compounds and time, as it allows miniaturization into 1536-well plates.”

Acoustic liquid handling saved them costly resources and allowed for miniatur­ization. The integrated process empow­ered complete oversight of assay-ready plates from order to delivery, both inter­nally and externally. An integrated Access DRS robotic platform, also available from Beckman Coulter Life Sciences, utilizing our acoustic liquid handlers prepared assay-ready plates and acoustic tube plates for HTS support.

Evotec significantly reduced cycle time, performing intermediary steps. They reaped transformative benefits, such as precise and accurate acoustic dispensing throughout. This saved time from store into plates with cherry pick or dose-response protocols running directly from tubes to destination plate. This also created com­pounding savings (nanoliter dosage al­lowed for minimal resource usage) and the flexibility to work with selected collec­tions. It should be noted that while acoustic liquid handling excels at contact-free nanoliter-scale transfers, at Beckman Coulter Life Sciences, we are strong pro­ponents of “right tool for the right job.” In that effort, the instrument is complemented well with larger-scale transfers. At Evotec, our Biomek i7 Workstation facilitated transfers from other storage media into compatible labware.⁶

Outside of traditional DMSO-based sample management, high-throughput DNA assembly is another application area that has been transformed by acoustic liq­uid handling. Codex DNA shares impres­sive statistics on workflow enhancements made by transforming their lab using acoustic liquid handling.

“Processes that would take 8 hours with traditional liquid handlers now take less than 30 minutes with the Echo Liquid Handler and tipless liquid handling, en­abling the construction of DNA variant li­braries at unprecedented scale,” said John E. Gill, Sr., Director of R&D at Codex DNA.⁵ “Moreover, the high accuracy and precision of non-contact acoustic technol­ogy transfers ensure that we’re delivering every oligonucleotide with utmost confi­dence.”

LOOKING AHEAD

Automated acoustic liquid handling allows labs focused on drug discovery to be active, agile, and responsive to evolv­ing demands and keep up with the in­creasingly complex pace of today’s laboratory. It also allows researchers to shift their focus from the tedium of the workflow to the research work at hand. As therapeutic technologies and discovery pipelines evolve, scalable platforms like acoustic liquid handling can help labs stay ahead of the curve.

In 2023, the global drug discovery market is estimated to be worth $93.91 billion with a 6.59%(CAGR) from 2023-2028.⁷ The tremendous investments and laboratory efforts being made to treat dis­eases and prolong life, paired with inno­vative solutions, can rapidly accelerate vital cures for complex, multi-faceted dis­eases, such as Alzheimer’s and cancer.

The drug discovery journey has fo­cused its innovation on speed and accu­racy. Critical breakthroughs in liquid handling automation offer a trajectory out of conflicting pressures, making it a prac­tical solution for labs. Though we may not be able to control inflation, we can strate­gically shorten the time it takes for life-sav­ing drugs to reach patient bedsides.

For those of us with loved ones who have suffered through illnesses, we uniquely know that reducing the time re­quired to discover a cure is priceless.

NOTE: Echo Automated Workstations are not intended or validated for use in the diagnosis of disease or other conditions.

REFERENCES

1. FDA. (2023, December 18). Novel Drug Approvals for 2023. USFDA. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023.
2. FDA. (2023, July 16). New Drug Therapies Approval 2022. USFDA. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022.
3. Deloitte (2023, July 16). Pharma R&D Return on investment falls in post-pandemic market https://www2.deloitte.com/uk/en/pages/press-re­leases/articles/pharma-r-d-return-on-investment-falls-in-post-pandemic-market.html.
4. For 700/sec: Echo65X_007 For 500,000: from 650 series IFU: 5.1 min /cycle of 1536:1536 100 nL transfer. Theoretical 24h throughput of 282 1536 plates: 433,512 at 100 nL stamp. Should be able to cycle 500K/24h with sub- 50 nL dispenses.
5. Beckman Coulter Life Sciences (2023, July 16). Echo Learning Center. https://www.beckman.com/liquid-handlers/echo-acoustic-liquid-han­dlers/echo-learning-center.
6. Beckman Coulter Life Sciences (2023, July 16). Echo Acoustic Liquid Han­dlers. https://www.beckman.com/liquid-handlers/echo-acoustic-liquid-handlers.
7. Mordor Intelligence (2023, July 16). Drug Discovery Market Size and Share Analysis – Growth Trends & Forecasts. https://www.mordorintelli­gence.com/industry-reports/drug-discovery-market.

John Fuller is the Commercial Product Manager for Echo Instruments at Beckman Coulter Life Sciences. He was previously a Field Applications Scientist for Labcyte. He holds a PhD. from the U.N.T Health Science Center and completed a postdoctoral fellowship at Johns Hopkins University School of Medicine.