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High-throughput screening

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High-throughput screening (HTS), is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry.

Purpose and method Edit

Through a combination of modern robotics, data processing and control software, liquid handling devices, and sensitive detectors, HTS allows a researcher to effectively conduct millions of biochemical, genetic or pharmacological tests in a short period of time. Through this process one can rapidly identify active compounds, antibodies or genes which modulate a particular biomolecular pathway. The results of these experiments provide starting points for drug design and for understanding the interaction or role of a particular biochemical process in biology.

In essence, HTS uses a brute-force approach to collect a large amount of experimental data -- usually observations about how some biological entity reacts to exposure to various chemical compounds -- in a relatively short time. A screen, in this context, is the larger experiment, with a single goal (usually testing a scientific hypothesis), to which all this data may subsequently be applied.

A key piece of HTS equipment is a plate: a small container, usually made of plastic, that features a grid of small, open divots called wells. Most of the wells contain experimentally useful matter, often a solution of dimethyl sulfoxide (DMSO) and some other chemical compound, the latter of which is different for each well across the plate. (The other wells are empty, intended for use as optional experimental controls.)

To prepare for an assay, the researcher fills each well of the plate with some biological entity that he or she wishes to conduct the experiment upon, such as a protein, some cells, or an animal embryo. After some incubation time has passed to allow the biological matter to absorb, bind to, or otherwise react (or fail to react) with the compounds in the wells, measurements are taken across all the plate's wells, either manually or by a machine. Manual measurements are often necessary when the researcher is using microscopy to (for example) seek changes or defects in embryonic development caused by the wells' compounds, looking for effects that a computer could not easily determine by itself. Otherwise, a specialized automated analysis machine can run a number of experiments on the wells (such as shining polarized light on them and measuring reflectivity, which can be an indication of protein binding). In this case, the machine outputs the result of each experiment as a grid of numeric values, with each number mapping to the value obtained from a single well. A high-capacity analysis machine can measure dozens of plates in the space of a few minutes like this, generating thousands of experimental datapoints very quickly.

Depending upon the results of this first assay, the researcher can perform follow up assays within the same screen by "cherrypicking" liquid from the wells that gave interesting results (known as "hits") into new assay plates, and then re-running the experiment to collect further data on this narrowed set, confirming and refining observations.

A screening facility typically holds a library of stock plates, whose contents are carefully catalogued, and each of which may have been created by the lab or obtained from a commercial source. These stock plates themselves are not directly used in experiments; instead, separate assay plates are created as needed. An assay plate is simply a copy of a stock plate, created by pipetteing a small amount of liquid (often measured in nanoliters) from the wells of a stock plate to the corresponding wells of a completely empty plate.

Automation is an important element in HTS's usefulness. A specialized robot is often responsible for much of the process over the lifetime of a single assay plate, from creation through final analysis. An HTS robot can usually prepare and analyze many plates simultaneously, further speeding the data-collection process. HTS robots currently exist which can test up to 100,000 compounds per day (Hann 2004).

HTS is a relatively recent innovation, made lately feasible through modern advances in robotics and high-speed computer technology. It still takes a highly specialized and expensive screening lab to run an HTS operation, however, so in many cases a small-to-moderately sized research institution will use the services of an existing HTS facility rather than set up one for itself.

There is a trend in academia to be their own drug discovery enterprise. Facilities which normally only industry had can now increasingly be found as well at universities. UCLA for example features an HTS laboratory (Molecular Screening Shared Resources (MSSR, UCLA)) which screens up to 100,000 compounds a day on a routine basis.

References Edit

  • Burbaum JJ, Sigal NH., New technologies for high-throughput screening, Curr Opin Chem Biol. 1997 Jun;1(1):72-8.
  • Hann, M.M., Oprea, T.I. Pursuing the leadlikeness concept in pharmaceutical research. Current Opinion in Chemical Biology. 2004, 8, 255-263.
  • Liu B, Li S, Hu J., Technological advances in high-throughput screening, Am J Pharmacogenomics. 2004;4(4):263-76.

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