Role of Model Organisms in Drug Discovery

Simple and easily accessible organisms can be used for probing gene function because of the conservation of gene function and sequence between widely divergent species. Commonly used organisms include the mouse, chicken, frog, zebra fish, nematode worm (C. elegans) and unicellular yeast (S. cerevisiae). Particularly useful are C. elegans and S.cerevisiae because their genomes have been completely sequenced. The mouse has the advantages that it is a mammal, some genetics is known, transgenic knockouts can be made and some genomic data are already available. The disadvantages are that it is costly and the generation time is long. Evidence for the usefulness of model organisms in functional genomics comes from search of known human disease genes in model organisms and the finding that majority of known disease genes have counterparts in lower species. This common origin is reflected not only in the high degree of conservation of genes between organisms but also in the role of genes in signalling networks. In many cases, the same proteins interacting in the same manner are involved in analogous processes in different species.

Comparative genomics enables tests to be performed quickly in organisms with simple genomes such as the fruit fly or algae to predict and guide the analysis of gene function in organisms with complex genomes such as humans.
The ease with which genes can be underexpressed or overexpressed in these model organisms enables studies of gene function to be performed in a short time. Because the early developmental stages of model organisms are easily accessible, it is possible to examine gene expression during embryogenesis to obtain clues to function. Functional homology can be tested in species such as Drosophila that are amenable to genetics.
It is important to identify all components of a genetic pathway where a particular gene functions. This knowledge is important if the disease happens to be due to a mutation in a gene that cannot be corrected and it becomes necessary to activate or inactivate the genetic pathway downstream of the mutant gene as a strategy for treatment.
Multicellular organisms, such as C. elegans, offer numerous biological advantages in programmes such as drug discovery, toxicology and basic research because of its remarkable similarity to the human genome. Over 70% ofB20 000 genes in C. elegans, are also found in humans and 70% of the 300 most important human disease genes have homologues with that of C. elegans. More is known about the biochemistry and genetics of C. elegans than any other animal. Since much of the genetic makeup of C. elegans also occurs in humans, laboratories in pharmaceutical companies and universities worldwide are modelling human diseases in these organisms. Their goals are to find new drug targets and to screen drug compounds in vivo using these biological systems. This information has been used to manipulate the nematode genes to create a ‘human disease model’. Disease-model C. elegans develops abnormally and has an abnormal size for its stage of development. These model organisms can be exposed to drugs and changes can be monitored.

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