One of the first reported systems for liquid handling was described in 1875 by Thaddeus M. Stevens, a professor in Analytical Chemistry at the College of Physicians and Surgeons of Indiana. The device was designed to control the flux of water through a filter paper to wash a filtrate. Although relatively simple, the apparatus was tackling present day needs: to save time and resources and improve performance through the elimination of human error. In the following decades, the field of laboratory automation did not develop much: most of the instruments were built in-house and designed for dedicated applications, limiting their usefulness to small audiences. Things changed during the first and second World Wars when the military establishment devoted resources to developing analytical instruments to accelerate tasks such as rapid gas analysis. These devices had two primary goals: to speed up specific procedures and to allow unskilled personnel to perform rather complex technical tasks. The dawn of automatic liquid handling had still to wait until the introduction of reliable devices for pipetting small volumes of liquids, which become available in the 60’s.
70's & 80's - The Introduction of Automated Liquid Handling
The 70’s saw the introduction of the liquid handling automation systems by adding a motor to a pipetting device. However, since there was no controlling module, the utility of these setups was somewhat restricted, and the scientific community did not widely adopt them. Liquid handling systems did not become more flexible and, therefore, useful to a broader audience until the introduction of the personal computer needed to operate sophisticated control modules.
During the 80’s liquid handling became automated with the introduction of electronic elements, which allowed the performance of complex protocol in workstations. These instruments had plates arranged in a specific order on a deck and a robotic arm carrying a liquid dispensing unit shuttling between them. In the early 80s, the Hamilton Company and Tecan both launched automated liquid handlers with washable pipetting channels attached to a cartesian arm. Smithkline Beckman (now Beckman Coulter) developed the first liquid handler to incorporate an interchangable multi-channel pipette. In 1986, Packard Instrument Company (later acquired by PerkinElmer) started to market the Probe instrument, a liquid handling workstation equipped with a gripper arm able to move plates in different positions of the deck. The possibility of using the deck space in flexible ways paved the way to the development of automated instruments which could be used with multiple protocols, increasing their adaptability to scientists’ needs and, therefore, their adoption in biomedical laboratories.
90's- High-throughput screening Drive the Adoption of Automated Liquid Handlers
The 90’s quickly became the years of the high-throughput screening. The evolution of liquid handling instrumentations allowed their extensive use in the pharmaceutical drug discovery pipeline. Fueled by the incredible success of combinatorial chemistry in providing vast numbers of molecules to be tested, the automation of drug development laboratories expanded at a furious pace. A significant focus became the capability of a specific instrument to integrate with other elements in the lab to facilitate the seamless processing of high numbers of samples. These better, more integrated electronic components allowed the instruments to become more precise and reliable. The possibility of integrating other units (e.g., optical readers, temperature control elements, shakers, and so forth) in the automated liquid handling workstations also introduced the concept of walk-away automation, allowing scientists to obtain results directly from the instruments for specific readouts. In short, automated liquid handling workstation started to morph in small, self-contained laboratories. Although customer interfaces were more intuitive than before, programming skills for setting up the required system correctly were needed. The requirement of dedicated highly specialized personnel to program, install, run, and troubleshoot these instruments was a significant limitation to the adoption of automation in many labs.
In the 2000’s, automated liquid handlers finally became mainstream. One of the drivers of the transition from specialty instruments to widely used systems was the development of sophisticated, user-friendly software interfaces allowing scientists to program their instruments quickly and intuitively. Better integration between the mechanical and electronic parts of the workstations led to improvements in the accuracy, speed, and efficiency of the workstations, increasing their intrinsic value in the lab environment. A second element pushing for the adoption of automation in laboratories stemmed from the advent of the genomic era heralded by the completion of the Human Genome Project. The dramatic development of next generation sequencing (NGS) technology resulted in an increased need for sample processing for DNA and RNA extraction and NGS library preparation. At the same time, proteomic science progressed almost at the same pace as genomics, requiring the reliable and precise manipulation of large numbers of samples in parallel. Manufacturers of liquid handling workstations started to develop systems capable of handling multiple applications and providing the output in formats compatible with the ever-changing requirements of the developing technologies. A significant focus became the capability of a specific instrument to integrate with other elements in the lab to facilitate the seamless processing of high numbers of samples.
2010's- Transitioning from Workstations to Workflows
The 2010’s have witnessed a move toward increased integration of multiple components in a single instrument. The scope of automated liquid handlers is no longer solely to transfer precise volumes of liquid from one plate to another, but to set up complex procedures and perform complete experimental tasks. In short, we are now witnessing the transition between workstations to workflows. An example of this new trend is the PerkinElmer chemagic™ Prime instrument, integrating the JANUS® G3 liquid handler with a chemagic™ 360 nucleic acid extraction instrument. The chemagic™ Prime instrument can transfer primary samples into the plates used for nucleic acid extraction, perform the entire procedure of DNA and RNA purification, and automatically set up samples for upstream analysis. Scientists using systems like the chemagic™ Prime instrument don’t need to interact with the samples until they are processed to the desired output format. The complexity of translating manual procedures into automated workflows is one of the barriers to the adoption of automated processes. Significant efforts have been devoted to the automation of experimental protocols allowing scientists to use these instruments as natural extensions of their day-to-day activities with plug-and-play procedures. Now users expect an intuitive automated workflow providing the output they need for any desired downstream application without having to devote time and resources to understanding how to make the system work.
The Future of Liquid Handling
The next step for automated liquid handling system is now the adoption of artificial intelligence to control different stages of the process and to exploit the full potential of internet connectivity to interact with users remotely. By relying on machine learning, software will be able to provide high levels of error management and adapt instrument activity to new situations which might occur during processing of the samples (e.g., compensate for nozzle clogging or react to a defect in a disposable tip). By communicating issues in real time to remote operators and describing their response to the problem, these workstations will be self-managed and represent streamlined walk-away solutions for the optimization of laboratory resources. The development of self-instructing software will also facilitate integration of different units, allowing labs to add or remove specific functional elements of an automated workflow. In turn, modularity will increase the overall flexibility of the system, allowing more diverse application of automated liquid handling instruments in biomedical laboratories.
Since its introduction as a system to regulate dripping of a fluid through filter paper, automated liquid handling has addressed the basic need of increasing experimental efficiency by processing large numbers of samples with speed and accuracy. The newest generation of instruments will have the ability to react to unexpected changes in protocols and conditions in a way comparable to human beings, paving the way for fully automated laboratories where robotized modules will perform most of the practical tasks.