AUTOMATED LIQUID HANDLING RESOURCE GUIDE
? Questions to Ask When Buying an Automated Liquid Handler
? The Benefits of Automated Liquid Handling for Microscale Samples
? Simplifying Lab Tasks with Automated Liquid Handling
? Automated Liquid Handlers for Chemical Screening
? Robotic Workstations and Automation in Drug Discovery
Questions to Ask When Buying an Automated Liquid Handler
Apart from performing many lab tasks more efficiently than manual options, automated liquid handlers (ALHs) offer several benefits.
For any applications that require repetitive pipetting tasks, such as serial dilutions, polymerase chain reaction (PCR), sample preparation, and next-generation sequencing, auto- mated liquid handlers (ALHs) are the way to go. Apart from performing these and other tasks more efficiently than manu- al options, ALHs have several other benefits, such as reducing the risk of cross-contamination and improving traceability with barcode scanning features.
7 Questions to Ask When Buying an Automated Liquid Handler:
What is the volume range?
Will it be used for many different applications and is it compatible with multiple labware formats?
What technology is used?
Will you need to automate plate handling, and will the instrument accommodate microplate stackers or robotic arms?
Does the ALH require specialized pipette tips?
Does it have other capabilities such as vacuum, magnetic bead separation, shaking, and heating and cooling?
How easy is the system to use and set up?
PURCHASING TIP
When shopping for an ALH, users will want to find out how reliable the system is and how easy it is to set up and run. Today’s ALHs are much easier to use than those of the past, and inexpensive options for labs that just need to automate a few key functions are more plentiful. However, purchasers will want to exercise caution as less expensive options can sometimes take a long time to set up and still generate workflow errors.
MANAGEMENT TIP
When implementing automation in your lab, it’s important to involve staff at the very beginning of the process and reassure them that they’re not going to be replaced by an automated system. Be sure to get their input when selecting instrumentation and highlight how automation will benefit them.
The Benefits of Automated Liquid Handling for Microscale Samples
Automating sample handling can fill a growing need for applications like DNA sequencing, protein expression, biological assays, and more.
by Kelsey A. Morrison, PhD
To many, the thought of handling microscale samples evokes an image of tedious manual pipetting. This time-consuming task can be largely replaced with automated manipulation of small samples. Automating sample handling can fill a growing need for applications like DNA sequencing, protein expression, biological assays, and the rapid development of synthetic products.
Despite the initial monetary investment necessary to acquire these systems, automated sample handling brings distinct advantages. Laboratories working with small samples by hand face worker fatigue, reduced precision, and limitations on experimental throughput. In contrast, investing in automation can bring obvious benefits, from reduced repetitive motion injuries to greater reproducibility, and increased processing bandwidth. Additional benefits include savings from fewer wasted samples and reagents, as well as streamlined workflows. The capability to combine sample preparation with analytical instrumentation for fully automated synthesis and analysis is another advantage.
Common types of systems for handling small-scale samples
Likely the most recognizable form of automatic sample handling, pipette-based systems act as robotic pipetting plat- forms by dispensing solutions from tips through contacting the deposition target. These pipette-based systems typically operate through either an air-cushion design for sample manipulation or with positive-displacement via pistons.
For applications requiring higher accuracy and precision of low-volume samples, positive-displacement is preferable over the lower cost, lower precision air-cushion mechanism.
Similar to the pipette-based sample handling systems are those based on syringes and pins, both of which require contact between the dispensing device and the intended end surface or solution. All three forms of contact-based liquid manipulation platforms have the potential drawback of cross-contamination.
For laboratories that can afford to invest in an automated sample handling platform based on mechanisms other than pipetting, syringes, or pin dispensing, the alternatives may be better options when high precision and accuracy are para- mount, if low- and sub-nanoliter samples are to be processed, or cross-contamination is a concern. A direct comparison
of results based upon data collected from samples handled in a tip-based system and in an acoustic droplet ejection (ADE) platform found statistically different results between both datasets, with the ADE system appearing to provide more consistent values. ADE sample handling is also useful for rapid, microscale synthetic prototyping, which is how it was applied for automatic reaction scouting of isoquinoline synthetic building blocks in nanoliter droplets. Microscale acoustic manipulation has a wide range of potential applications because of its precise control, short dispensing time, and compatibility with high-capacity sample wells rendering the mechanism, particularly appealing in bioassays.
Other forms of non-contact, high-precision liquid handling are systems employing microfluidics, solenoid microvalves, and piezoelectric devices for aliquot ejection as some of the major classes of liquid manipulation technologies. Beyond simply a liquid transfer device, automation of sample handling with microfluidics offers the possibility of higher-order sample preparation, such as sample mixing, separations, and other preparatory steps for small sample sizes. Automated liquid handling with solenoid and piezoelectric devices has demonstrated accuracy and precision that is highly suitable for sensitive assays, even for picoliter and nanoliter volumes.
Simplifying Lab Tasks with Automated Liquid Handling
Devices simplify and economize many basic lab processes.
by Mike May, PhD and Ajay P. Manuel, PhD
Most scientists or lab personnel with much experience pipetting—especially pipetting over and over—dream of automated liquid handling. This technology can be applied to a wide range of processes, from serial dilutions and cell culture to high-throughput screening and the polymerase chain reaction. Best of all, some platforms make automated liquid handling possible in almost any lab.
Not that long ago, most automated liquid handlers required lots of lab space, mountains of money, and an expert in robot- ic programming. That limited the users to large pharmaceutical companies and other organizations with deep pockets. Now, for a few thousand dollars and a little bench space, almost any lab can add automated liquid handling. Still, some obstacles must be addressed.
Overcoming obstacles
When asked about the most common challenges in auto- mated liquid handling, experts cite the fine-tuning and troubleshooting processes as the most difficult part of using lab robotics with the rounds of trial-and-error surrounding protocol codes taking the bulk of development time.
Other experts agree that usability should be considered in a platform. In fact, reliability and usability are considered the two most important criteria of an automated liquid handling system are usability and reliability.
In a premium commercial liquid handler, intuitive user interfaces and redundant systems ensure correct pipetting. Getting those benefits, though, comes at a series of costs, including being expensive to purchase, maintain, and requiring proprietary plasticware.
Conversely, not spending enough on a system can create other problems as some inexpensive systems for automated pipetting can take a lot of time to set up and still generate errors in a workflow. So, for many scientists, there is a need for balance—something at a low enough cost that provides the features required for a variety of uses. And cost really matters. Liquid handlers generally automate common manual lab tasks. As such, many researchers find it difficult to justify the acquisition of these machines with high price tags.
An array of advances
Beyond smaller and more affordable options for automat- ed liquid handling, it takes far less expertise to use some platforms. In fact, ease of use is a crucial improvement in this technology and the development of interfaces that provide for ease-of-use for non-automation specialists is a thriving aspect of study automation. Most scientists in the market for such technology should expect a platform that can be used without hiring an expert.
Advances in technology from other fields could also improve automated liquid handling. One example comes from ma- chine vision. Here, a camera and image-processing software control the pipettes. The machine vision can perform many tasks, from identifying the installed pipettes, if a well of a plate is empty, the location of plasticware on the platform, and so on. This helps minimize human intervention and setup time while increasing reliability. Although adding a camera increases a platform’s cost, it makes it easier for such a system to be less prone to errors and is easy to set up.
To really make this technology available in more labs and for more workflows, a platform needs to be affordable. That’s an ongoing improvement in parts of this instrument market, which is driving a wider range of applications, instead of just the high-throughput screening where automated liquid handling started.
Expanding the user base
Some less expensive but effective platforms already exist for automating liquid handling. Still, some do-it-yourself scientists will turn to other solutions. For some labs, the DIY approach to automated liquid handling just won’t fit the philosophy of the scientists. Some just don’t like to tinker as much as others, no matter how much money can be saved. When budget is less of a concern, it is also easier to purchase an automated liquid handling device. Overall, scientists can now choose from a variety of manufacturers in this product area. In addition, prices for commercial systems range from around $10,000 to one million or more—covering benchtop to industrial systems. To try out this technology, purchasing a used handler might make sense, and some platforms are available for less than $1,000.
So, there’s clearly a range of ways to implement automated liquid handling. Plus, this technology can improve a variety of workflows. The solution for a lab depends on many factors, from applications and required throughput to economics and expertise. To get started, it probably pays to start out small and see how automation works in a lab. Jumping into too much automation without the right preparation could be overwhelming, not to mention a path to a mistake. So, look around, ask around, and see what fits best for your lab.
Product Spotlight
microPro 300: The world’s smallest 96/384 channel semi-automated benchtop pipettor
This innovative compact instrument packs an enormous feature set that offers unprecedented capability and value. Multi-Function pipetting increases flexibility with functions to meet any user’s needs; from simple aspirates and dispenses to complex custom programs. An intuitive touchscreen user interface and a large, high-resolution screen provide for a friendly experience with all the features and functions right at your fingertips. A ring lock tip system allows for “easy touch” tip changes, without the need for unwieldy clamp handles. PDR (Pipetting depth recall) provides the user the means to set, store and utilize a virtually unlimited number of containers with completely customizable depth settings. Touchless tip ejection increases safety and reduces the risk of contamination. Saved programs are conveniently stored in the Favorites section and organized by name, type, and creation date. With a 10x Speed Control for all aspirate and dispense operations, the microPro 300 is accurate, affordable, efficient, reliable, and easy to use.
Automated Liquid Handlers for Chemical Screening
Outputs for liquid handlers cover a broad range of categories, including chemical library deposition, stepwise qPCR setup, and biochemical or cellular biology-based screening
by Brandoch Cook, PhD
The identification of new drugs from among an infinite combination of atoms and linkages has, for most of its history, been restricted by the slow crawl of low throughput intrinsic to the technology available. A classic example of drug dis- covery that has evolved along with gains in throughput is the identification of microtubule targeting agents (MTAs). For several hundred years, botanicals derived from the autumn crocus have been used to relieve gout and other inflammatory immune disorders. The active ingredient, colchicine, was identified and characterized in the 1940s, but its actual activity was not defined until the 1960s. Because colchicine treatment accentuates mitotic figures in cell preparations, allowing easy visualization, its use in research led to definitive proof that human cells have 46, not 48, chromosomes.
Forward chemical genetic investigations later linked a cellular function, mitosis, to the discovery of a protein, tubulin, via binding of colchicine. Another MTA, Taxol, was identified shortly thereafter, and surprisingly displayed an opposing function to colchicine, promoting rather than inhibiting microtubule polymerization. Like colchicine, Taxol is botanical in origin, from the bark of the Pacific yew. Because of the strength of its microtubule-binding activity, Taxol was used to biochemically pull down, purify, and characterize com- ponents of protein complexes that reside there along with tubulin. Throughout the next two decades, the anti-tumor activities of Taxol were investigated and defined, and since its initial Food and Drug Administration (FDA) approval in 1992, it has been used widely in chemotherapeutic regimens, particularly for breast and ovarian cancers.
The existence of two perfectly opposing MTAs in the limitless chemical wilderness prompts the tantalizing idea that there are many more out there. Perhaps problems like chemotherapeutic drug resistance can be overcome by using them in series or parallel, analogously to classes of antibiotics, or that activities and specificities can be optimized and toxicities minimized. The great contemporary leap in capability for chemical screening using an extensive natural product and synthetic libraries unlocks the possibility that investigators may actually find them. Hence, modern MTA drug discovery has evolved to incorporate assays with ever-greater sensitivity and throughput. Initial improvements relied on the detection of changes in refracted light sent through purified microtubule samples stained with nucleic acid-binding dyes. Recent improvements have increased sensitivity many-fold by using enzymatically applied fluorophore tags and auto- mating microscopic assays to detect slight changes in fluo- rescent emissions. As a result, there are many new candidate MTAs somewhere along the pipeline from the wilderness to the doorstep.
These developments have only been possible with the reduction of human error. To a certain extent, the more human hands manipulate things in the realm of the very small, the more they skew the results in ways that are, by contrast, very large. In chemical screening and many other high-throughput protocols, automated liquid handlers have stepped in where human hands would otherwise fail. Liquid handlers apply robotics and software to program and manipulate liquid distribution tasks into adaptable outputs. This can take a form procedurally indistinguishable from pipetting small volumes into microwell plates, but using movable arms and interchangeable stages by calibrating compressed air through plastic tips. It may also be something as divergent as automating the flow of bacterial colony picking, culturing, and genetic analysis, guiding robotics with sound waves. Consequently, outputs for liquid handlers cover a broad range of categories, including chemical library deposition, stepwise quantitative polymerase chain reaction (qPCR) setup, and biochemical or cellular biology-based screening using techniques such as enzyme-linked immunosorbent assay (ELISA) or flow cytometry. Because of the diversity of outputs, liquid handlers come in multipurpose formats that can be customized to different assays, or specialized formats adapted to specific repetitive tasks that can automate immunohistochemical staining, anti- body purification, and more.
In any high-throughput process, error and contamination can come from a wide variety of human sources: mis-pipetting into adjacent microwells; miscalculation of reagents in master mixes; or contaminants on gloves, tubes, or equipment that transfers into microwells. These errors can magnify discrepancies in final results; this is especially true with contaminating deoxyribonucleic acids (DNAs) that can be mis-amplified in qPCR reactions. Discrepancies in consistency between manual and automated protocols are not only a boon to research science and reproducibility—these differences can have real, life-or-death implications.
Accurate and rapid identification of pathogens or emerging disease vectors have the potential to mitigate food-borne illness or tropical disease outbreaks. Projects to streamline DNA profiling workflows can minimize errors in the identification of criminal suspects. With the application of robotics to steps where it is becoming increasingly necessary to do so, researchers can devote themselves more fully to the tasks of data collection and analysis, where robots are not quite ready to tread.
Robotic Workstations and Automation in Drug Discovery
What would a manager in a drug discovery lab like to see in automation products?
by Angelo DePalma
High-throughput screening (HTS) for drug discovery was conceived through the nearly simultaneous industrialization of combinatorial chemistry and the emergence of affordable laboratory automation, but its success ultimately depends on integrating factors related to chemistry, assay design, and informatics. Combichem enabled the creation of compound libraries with millions of compounds, while laboratory robots, plate handlers, liquid handlers, and supervisory information systems allowed their study.
Today, drug discovery remains a game of big numbers. John Unitt, director of bioscience at Sygnature Discovery (Nottingham, UK, and Cambridge, MA), notes that deep-pocketed companies routinely investigate libraries in the one- to-two-million-compound range, while smaller discovery organizations use much smaller libraries of only 200,000 to 400,000 molecules.
Robotics has more than kept up with the compound flow, so automation vendors now differentiate based on accessibility, breadth of the assay (i.e., instrument and method flexibility), and software, while library vendors focus on creating col- lections of original chemical scaffolds. Meanwhile, a whole separate industry works on automating and—perhaps more importantly—standardizing optical readouts, liquid handling and dispensing, and background tasks like cell culture and preparation.
For low-throughput applications such as assay construction and metabolic, pK, and ADME studies, Sygnature uses a small-footprint system with two pipetting options and built-in flexibility. They chose this system for its throughput, breadth of assay, and walkaway time.
For liquid dispensing, they use an acoustic dispenser to pre- pare assay test plates using nanoliter volumes of compound solutions. Using acoustic dispensing conserves highly valuable compound stocks while optimizing liquid handling performance with excellent accuracy and precision.
For their robotics platform, Sygnature relies on a benchtop automation system that provides entry-level, deploy any- where automation and easy integration with plate storage units. Drug discovery labs might also want to invest in the integrated storage unit and cell culture units as well, in addition to informatics to communicate and capture all data generated during screening. With this modular platform, Sygnature can grow and expand the system in terms of assay readouts, end points, and capacity.
Despite still relying on huge molecule collections, HTS is no longer merely about compound library size. The emphasis, Unitt notes, is on quality versus quantity. “For our projects, senior medicinal chemists assess all structures for chemical diversity and lead-like structures while emphasizing synthetically novel scaffolds.”
Quality has become a priority for library developers because, in the past, compound collections included entries with significant side products and impurities. False positives and negatives resulting from unanticipated, unknowable interactions between impurities and targets can thwart the potential for mining a collection of hits for structure-activity relationships, which discovery scientists use to generate lead molecules and eventually drug candidates.
What would a manager in a drug discovery lab like to see in future automation products? “We’re always looking for ways to do things faster,” Unitt says. “Accuracy and precision of existing automated systems are already very good, so the emphasis should be on customer support to minimize downtime.”
One key to the success of HTS is the application of assays that ask the right questions of the right compound library. “If an identifiable bottleneck exists, it is adapting a standard laboratory test—immunoassay, enzyme inhibition, etc.—to microplate formats and successfully marrying that assay to the robotic workstation,” Unitt explains. Assay developers have made great strides in this area, “but over the years, HTS has overcome problems like these as more and more screening platforms have been adapted to it.”
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