Bridging the Gap
Translational research is trying to bridge the gap between model systems and human biology. It covers a wide range of disciplines including clinical research, biomarker discovery, medical imaging, use of transgenic animals, and mapping of pathways.
Selection of the right targets for drug discovery is one of the key decisions in pharmaceutical and biotechnology research and development. Starting with the wrong target will generate a lot of expense without the possibility to make a drug in the end.
A target can be wrong for many reasons: not relevant to the disease, different in animal systems compared to human, subunit composition is different in various cells, or the assay does not reflect the true situation in the diseased tissue.
Clues as to a target's involvement in disease (target validation) can be obtained by using different in vitro and in vivo approaches, including analysis of the pattern of expression of the target in normal and diseased tissue, gene modulation using molecular biology techniques, studies using different target modulators, genetic studies, functional tests in cells and tissues, and transgenic animal models.
One of the major problems in working with drug targets is determining whether the different models used are comparable and truly predictive (assay validation). To form a solid basis for mechanistic understanding and thus for "go/no-go" decisions, the fully functional target must be studied.
Mechanisms at the molecular level can be studied by many methods. Biochemical assays are used to understand activity of proteins in vitro. Binding of small molecules to proteins can be studied by a number of techniques, including calorimetry, fluorescence microscopy, chromatography, and spectroscopy.
The structure of proteins can be determined by x-ray crystallography and NMR. However, many of these methods require the purification of proteins, which means that studies are performed outside the proper context.