Genomics and New Target Identification

Drug companies have recently become involved in the use of genomics to identify new genes which might have some role in disease pathology. Molecular biologists can seek mutations or alterations in genetic signatures which are predictive of the targeted disease in a large population. If this mutation is always associated with the disease, they can then map this gene to the disease. This is known as 'linkage analysis'. When linkage analysis can predict that a disease-regulatory gene falls within a certain region of a chromosome bounded by other known genes, scientists can determine the genetic sequence of the causative gene. This process is known as 'positional cloning' because the cloning begins and ends at certain chromosomal locations. Positional cloning, coupled with global epidemi-

ological studies and linkage analysis, will provide molecular targets for the few diseases which are derived from hereditary alterations in the human genome, often the result of inbreeding in isolated populations. An example of new target identification using these methods was the identification of ApoE as an important causative factor in Alzheimer's disease (Pericak-Vance et al 1991).

The pharmaceutical industry can further exploit this genomic technology by choosing specific diseases, performing epidemiological research to find families with patterns of hereditary disease, and mapping the transmission of the disease to find the specific genes that cause the pathology. Genes are then identified using positional cloning.

However, other researchers are not closing in on suspected mutations, but identifying all the genes expressed by human cells, and then sequencing short segments of each one. These 'expressed sequence tags' (ESTs) can then used as starting points to derive full-length cDNA for a newly identified gene.

Genomics may, with the completion of the Human Genome Project, become a mainstay of new target identification for drug discovery. The Human Genome Project is a consortium of government and industry-funded laboratories, which se-quenced the entire human genome using both EST and positional cloning methods. This project identified and sequenced all of the estimated 60,000 to 30 000 -100 000 human genes (3 billion nucleotides) by the year 2001.

At the time of writing complete genomic sequences are available for atleast 141 viruses, 51 organelles, two eubacteria, one eukaryote and most mammalian mitochondria. Several organisms for which complete genome data are available include Haemophilus influenzae, Mycoplasma geneta-lium, and Saccharomyces cervisiae. The volume of this information may be illustrated by almost the simplest case: the yeast, S. cerevisiae contains approximately 6000 genes (Schuler et al 1999), the sequences of which are available to scientists at FTP sites on the internet. It is expected that by maps for the common bacteria E. coli and B. sub-tilis, and the C. elegans will also be complete and soon publicly available.

The sequencing of unknown genes will not directly identify new molecular targets for disease. However, the availability of sequences will permit rapid identification of genes once a target protein is identified, without having to sequence more than a few peptides of the protein. The access to gene sequence information should shave months off of the discovery process, allowing rapid cloning of new targets for assay development.

Genomics and epidemiology will identify genes that are altered or mutated in certain diseases. However, this molecular biological breakthrough will not permit the mapping of a function to the genes. That task is assigned to the cell biologists, who will have to study basic cellular mechanisms with normal and diseased genes, or study transgenic animals expressing the disease-specific gene in certain tissues, before a function can be attributed to the newly identified gene.

Yet another group of biotechnology companies is exploiting this niche, to provide 'functional genomics' services which allow identification of biological functions associated with their clients' newly-identified disease genes. Functional genomics takes advantage of cell or developmental biology, and measures the effects of modified vs. normal gene sequences in functional assays. These functional assays are not, themselves, drug screens. They are methods of validating new targets, which must then be developed further for the discovery of drugs.

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