The classical way of developing a drug for a specific disease is to test a number of drug candidates and see if any of them reduce or entirely remove the symptom of the disease. Understanding why the drug works is of less importance. This good old trial-and-error strategy is known in the pharma industry as phenotypic drug discovery. The expression originates from the word phenotype – an observable characteristic of an organism, e.g. hair color.

In the 1990s the reverse approach became popular. From a hypothesis of what is causing the disease, researchers search for a drug that specifically targets the disease causing compound, often a protein. Using a method known as high-throughput screening, a huge number of drug candidates are screened in a brute-force fashion for the desired effect on the target compound.

High-throughput screening

Glossary

Phenotype

Observable characteristic of a cell or an organism

Phenotypic drug discovery

Classical trial-and-error drug development strategy

Target-based drug discovery

Modern hypothesis-based drug development strategy

High-throughput screening

Brute-force search method for finding drug candidates

High-content screening

Cell-based phenotypic method for finding drug candidates

Fluorescent labels

Toxic stains used to charac­terize cells

Label-free

Term used to indicate that fluorescent labels are not used

This new approach, target-based drug discovery, works well with straightforward diseases. But, as the pharma industry has been reminded of, biology is surprisingly complex. In most diseases many compounds and biological processes' are involved, making target-based drug discovery less effective for such complex but common diseases.

During the past decades the pharma industry has experienced a decline in productivity. It is becoming increasingly clear that the limited success of target-based drug discovery has contributed to this decline. Phenotypic drug discovery is therefore experiencing a revival, in a modern form using a method known in the industry as high-content screening or high-content analysis. By using computerized imaging, high-content screening allows researchers to study the behavior of cultured cells and their complex response to drugs in a high-throughput manner.

However, to be able to computer-process the recorded images, high-content screening requires that the cells are stained with chemical labels. Unfortunately, these fluorescent labels release toxins and fade when imaged, making high-content screening unsuitable for observing living cells.

The current form of high-content screening is based on conventional microscopy. The core technology of the HoloMonitor® products, holographic time-lapse microscopy, creates 3D-movies of unstained living cells that can be computer-processed without requiring the use of toxic labels. This new ability opens the door to more realistic high-content screening of living cells and their behavior over time – label-free high-content screening.

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