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High
throughput screening (HTS) involves performing various microplate-based
immunoassays with compounds generated from synthetic combinatorial
chemistry techniques or from natural product isolation. Assays
are developed to simulate a specific biological receptor or
function, and a qualitative decision is generated ("hit"
or "miss").
The
demands for high capacity and high throughput are presently
met by the combination of three essential components:
- Robotics-feeding
liquid handling workstations
- Inventory
control via sample management and logistics (plate stackers)
- Data
management and analysis software
Particular
assay types are more amenable to continuous and around the
clock operation, such as scintillation proximity assay (SPA),
enzyme-linked immunosorbent assay (ELISA), fluorescent intensity
(FI), chemi- and bio-luminescence and absorbance/colorimetry.
Other screening assays, such as those based on electrophoresis
or cell morphological change, are difficult to fully automate
due to special cell-handling conditions or incompatibility
with robots. In these cases a semi-automated approach is more
feasible using a 96-channel pipettor, such as Quadra96™
(Tomtec), Hydra96™ (Robbins) or Multimek96 (Beckman Coulter).
Sample
preparation performed for HTS involves reagent and sample
liquid handling procedures, and frequently a timed incubation
step at a controlled temperature is required. Automated hit
picking is a hardware and software application that automates
the transfer of lead compounds from their source plates onto
destination plates for consolidation. These procedures commonly
use both 96- and 384-well plates.
A
multiple channel liquid handling workstation is ideal for
both the initial high throughput screening procedure and for
hit picking once the hits are identified. These tasks are
exemplified by Genesis Series Workstations (TECAN Group Ltd.,
Mannedorf, Switzerland) integrated with a Genesis Te-MO 96
(a 96-channel multi-pipetting head) and a robot manipulating
arm to shuttle plates around the deck.
A
similar system is the Biomek FX (Beckman Coulter, Fullerton,
California USA) which is configured with an interchangeable
96- or 384-channel disposable tip pipetting head and an 8-channel
independent head. The system uses one head to add controls
to designated wells and the second head to add reagents to
the entire plate.
Automation
of this task via 8-, 12- and 96-channel liquid transfers is
also offered by the Staccato Screening Assay Workstation (Zymark,
Hopkinton, Massachusetts USA) which integrates the SciClone
advanced liquid handler (ALH) and Presto Autostack to offer
high-speed plate reformatting using 96- and 384-well plates.
The
demand for even greater throughput in screening procedures
("ultra" high throughput) often requires a larger
industrial process rather than a laboratory workstation approach.
The Allegro™ system (Zymark) interconnects independent
workstation modules consisting of storage and incubation carousels,
washers, liquid handlers and readers in an assembly-line format.
Modules are simply added to put in more steps or increase
capabilities. This system is capable of running 1,000 96-well
plates (96,000 assays) per day and is 384-well plate compatible.
The
Asset system (The Automation Partnership, Hertfordshire, UK)
is a larger volume example of a fully integrated automation
solution that can test 200,000 compounds in one working day.
Other industrial HTS systems are available from Aurora Biosciences,
Evotec and Roche/Zeiss/Cellomics.
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