Handling High-Throughput Screening: Liquid Handlers
Author: Nathan Colbert
Learning Objectives
- Recall the history of liquid handlers
- Describe modern-day usages of liquid handlers
- Evaluate the pros and cons of using liquid handlers
Graphical Abstract
Legend. Shown above are two different styles of liquid handlers. To the left is a robotic arm using micropipettes to transport one volume of liquid at a time, the different reagents and plate destinations below the arm. To the right is a 96-well pipetting handler, capable of transporting 96 volumes of liquid at once in between the white 96-well plates below the pipettes in the picture. Image created with Canva Pro.
Introduction
The human race has been invested in biotechnological research for centuries. Whether this focuses on more basic chemistry fundamentals or very convoluted genome processing, our continued interest has led to a never-ending pursuit of discovery. With this long-term research and discovery also comes the motivation to enhance the ease of the methodologies used on all fronts. A specific requirement and methodology of biotechnological research arose over time, that being the need to handle smaller and smaller amounts of liquid compounds for experimentation. For reasons of precision, reproducibility, and variance, experiments began leaning on this and motivating the field to discover reliable and simpler ways to scale down experiments to the level of microvolumes.
Background
For ease of dealing with smaller and smaller volumes, liquid handlers were developed to assist human capabilities in biotechnology. The origins of the pursuit and design of liquid handling can be dated back to the late 18th century. In 1795, a French Chemist named Descroizilles created the first burette and pipet combination. This device and associated advancements were simply small graduated cylinders with the capability of dispensing small, tabulated volumes of liquid at a time. (1) Over the next century, research methods developed and improved, these primitive liquid handling devices following. In 1947, Clark Hamilton developed the first syringe capable of dispensing microvolumes, a renowned technological advancement that showed what 150 years of scientific development at that time could achieve. (1) With the progression of time also came the advancement of discovery techniques, and as decades passed, the definition of liquid handler continued to develop. From the first mechanization techniques in the 1950s all the way to the creation of the first motor and microprocessor technology in the 1980s, liquid handling could now be fully automated. In 1990, a company called TomTec Inc. continued the advancements by creating an automated 96-channel liquid handling device, capable of moving 96 separate microvolumes at once. (1) The image of this liquid handler, following a path of 200-year development, brings us closer to the modern-day definition and usages of liquid handlers.
Modern-day
Today, liquid handlers can also be called liquid-handling robots, which can come in a variety of sizes, from smaller benchtop use to usage by industrial processes. While micropipettes and syringes still exist and are used widely, their capabilities now appear trivial to those of very advanced liquid-handling robotics. Modern-day liquid handling is now almost entirely associated with automation, since certain experiments exist that are fully dependent on these technologies. One example is in the determination of protein structures, which relies on monitored expression of 25,000 different genes. Since the precise temperature, pH, and solution composition for optimum structural definition cannot be known, a very large combination of different varieties of these conditions must be measured concurrently. (2) Liquid handling robots are also completely necessary to the field of drug discovery, which sometimes starts at having a library of thousands of compounds whose effect on a bacterium or virus will need to be discovered. In addition to the many different compounds, other factors that may be integral also include pH, temperature, solution composition, as well as the concentration of compounds themselves. (2) Without the aid of liquid handling robots that are capable of dealing with microfluidics in hundreds of plates at once that can each have 1536 wells, these discoveries would be impossible. While liquid-handling can be utilized for industrial-scale experiments like these, the technology can also be acquired and used by smaller laboratories to provide more ease in dayto- day experiments. These include the preparation of reagents within 96-well plates for PCR reactions and analysis, DNA sequencing, or smaller-scale drug discovery. Depending on human capabilities and the use of handheld micropipettes to combine thousands of different combinations of compounds would lead to the loss of decades, even just for one experiment.
Pros and Cons
While liquid handling technology does appear to provide vast improvements to biotechnological research across the board, it is important to more closely evaluate the precise pros and cons of these devices. Many of the pros have already been discussed, including the ability to miniaturize experiments on a scale that allows for thousands of combinations of compounds and conditions. Without liquid handlers, experiments designed along these lines would be impossible to carry out. An additional positive is the degree of precision and reproducibility that the use of liquid handlers can provide. (3) If the function of the robotic liquid handlers is entirely trusted, then the possibility of human error in the setup of complicated experiments can be removed. Additionally, the reproduction of experiments in order to demonstrate their validity to the scientific world is much easier to carry out, since the only requirement would be to apply the same code to the handler and run the experiment again. Another pro would be the design of many liquid handlers, which are usually housed within a closed case, sometimes with the addition of a HEPA filter. Having an environment closed off to potential contamination only further cements the validity of the experiments performed. When focusing on the negative aspects of liquid-handling technologies, the main concern revolves around the cost. Depending on the robustness of the machine desired, the need for more direct ease of experimentation from day-to-day will have to be weighed against spending anywhere from $5,000 to $30,000 or more. (3) If the experiments required are not industrially sized and do not completely require automation, conceding on this capital cost may not be worth it. It is important to review your own lab’s specific needs regarding high-throughput design and extra efficiency. (3) Additionally, while it can be seen as an advantage to rely solely on the actions of a robotic system to prepare and conduct experiments, it is important to understand the possible negative outcomes. While robots work efficiently when designed and coded correctly, automation issues can arise and delay experiments. While some of these issues may be immediately evident, such as a machine alarm or a mechanical problem, certain issues with volumetric dispensing or code instructions may go unnoticed. If handlers are used to save time and remain unmonitored, issues like these could become inherent to their experiments and lead to incorrect results. While liquid handlers can save a lot of time, errors with experiments that are set up at their scale can also lead to an immense loss of time.
Conclusion
Liquid handlers have evolved over the past 200 years from being very simple devices designed to ease the transport of precise liquid volumes into the industrially sized robots that allow for the carrying-out of once impossible experiments. Their benefits to the fields of protein characterization and drug discovery have only led to the further exponential increase of scientific development. (1) While used at an industrial scale, liquid handlers have also been developed for use in smaller scale laboratories; here they can increase efficiency and provide a greater ease of experimentation for common research methods. While the initial cost of these machines is high, their benefit is very much worth it, as long as the requirements and robotics are fully understood.
References
- Martin, J. A. (2009, June 19). The history of automated liquid handling . Retrieved April 30,
2020, from http://diyhpl.us/~bryan/irc/labautopedia-history-of-automated-liquid-handling.html - Kong, F., Yuan L., Zheng, Y. F., Chen, W. (2012). Automatic Liquid Handling for Life
Science: A Critical Review of the Current State of the Art. Journal of Laboratory Automation,
17(3), 169-185. DOI: 10.1177/2211068211435302 - Thinking about automating your liquid handling? (2015, February 5). Retrieved April 30,
2020, from https://www.biocompare.com/Bench-Tips/171286-Thinking-about-automatingyour-
liquid-handling/
Questions
- What are liquid handlers? Liquid handlers are devices capable of transporting (handling)
smaller volumes of liquid. These can be handheld mechanical devices or larger scale
automated devices capable of handling thousands of separate volumes at once. They
mainly relate to the field of biotechnology with the combination of compounds and
reagents for experiments, such as drug discovery. - Why are liquid handlers important? Liquid handlers are important because they allow for
very complicated and sometimes impossible experiments to be performed. Certain
designs require thousands of combinations of microvolumes of liquid, something a human
being is incapable of doing on their own. Liquid handling robots allow for large scale
industrial biotech experiments to be performed without the need for human intervention. - Describe modern-day usages of liquid handlers. Liquid handlers can be used for large
scale protein structure determination as well as drug discovery experiments. Additionally,
smaller labs can use them to ease day-to-day experiments and increase efficiency. - Reflect on the historical timeline of liquid handler development. What does this show about
modern-day science and possible future developments? With the first pipette of sorts
being developed before 1800 and it taking 200 years to reach any sort of automation, the
past 20 years of further development show exponential growth. If the modern-day field of
science has experienced such growth to fully change the array of possibilities for liquid
handling technologies past anything those researchers 200 years ago could have
envisioned, then the next decades will undoubtedly continue to change the game. If the
advancements are anything like what science has experienced in my lifetime, then they
will be unpredictable. - How do liquid handling technologies relate to social and environmental justice? Liquid
handling technologies and their potential of future development paint a future where the
ability for drug development based on a high-throughput design may become so easy that
they can become household items and used by anyone. With the development of the
biotechnological field over the next century as well as the arising or more virulent diseases
or ailments, liquid handlers for drug discovery and design may become necessary for daily
life. This brings about questions of how expensive these technologies may be in this
dystopian future and what races or classes of people will have easier access to them. The
applications of the concepts of social and environmental justice are important here, since
if these technologies become a necessity to human health then they will need to be
available to everyone, no matter how rich or how poor. Hopefully, as the field of science
develops, so too can the public understanding of environmental justice.