Model Organisms in Drug Discovery

SCREENING THE GENOME EFFECTIVELY 255
proteins. Indeed, one could argue that all human disease or disease treatment
pathways of interest probably contain druggable genes, so that by mutating all
the druggable genes in the genome one can interrogate all pathways for points
of therapeutic intervention.
Demonstrating the scale at which mammalian genes can be mutated, we
have industrialized gene knock-out technologies for saturation of the
druggable genome within the next 4 years. We have implemented our genome
5000 program to knock out and analyze the resulting phenotypes for 5000
genes from the mammalian genome. The 5000 genes chosen are all members of
the currently druggable gene families. Because others have suggested that the
druggable genome may be as small as about 3000 genes (Hopkins and Groom,
2002), this scale is sufficient to saturate the mammalian druggable genome in
order to identify those genes that have the greatest potential for human
disease treatment.
10.3 Screening the genome effectively for novel drug targets
Given the possibility of generating knock-out mouse lines at a rate of 1000
per year, the next challenge is to implement a biological evaluation process
that has a high probability of identifying potential drug targets, as assessed by
the physiological consequences of gene disruption. We have developed a
process that maximizes our potential to identify therapeutically significant
genes.
This process represents the application of increasingly fine filters to genomic
information. First, the genome is mined for members of druggable families.
Second, knock-out mice are generated for selected genes at an average rate of
20 lines of mutant mice per week. A minimum cohort for initial evaluation is
16 animals; 8 homozygous nulls, 4 heterozygotes and 4 wild-type animals for
each gene. This cohort size has produced reliable data from the primary screen
upon which decisions for secondary screens can be made. Implementation of
this plan has necessitated the integration of bioinformatics, mouse genetics,
robotics and high-speed physiological evaluation in a unique and robust
infrastructure that has demonstrated already the ability to operate at the
required rate. The logistics of generating, maintaining, genotyping and
characterizing the required number of animals have been satisfied.
Our first biological evaluation of the animals is a comprehensive clinical
assessment of all the physiological parameters that we can measure effectively
in high-throughput mode. Each test has direct relevance to one or more of our
therapeutic areas and is designed to yield information that can be correlated
directly with therapeutic intervention. This process includes an extensive
battery of behavioral evaluations (neurology), blood pressure and heart rate
measurements (cardiology) and a complete hematology survey supplemented