Author: Gilbert S. Omenn

In a recent article in Molecular Systems Biology, Leroy Hood's group at The Institute for Systems Biology in Seattle and George Carlson's group at the McLaughlin Research Institute in Great Falls, Montana, presented a comprehensively annotated analysis of the initiation and progression of prion disease in the mouse (Hwang et al, 2009). This paper is likely to become a landmark in systems biology, both for its design and specific methods and for its novel findings.

Since the emergence of 'omics technologies,' global analyses of gene expression (mRNA) and proteins have yielded increasingly long lists of disease-associated molecules. Distinguishing true-positive from false-positive signals and organizing the findings into pathways, networks, and modules related to histopathological and clinical phenotypes in temporal and spatial dimensions is an overwhelming set of challenges. The task is quadrupled by the complexity of the brain, the peculiarities (if not mysteries) of the transmissible protein agents of prion diseases, and the variability in both prion properties and genetic make-up of infected organisms.

Remarkably, these problems were turned into levers to enhance the studies by Hwang et al. With two prion strains, characterized by different incubation times, and mice from six different genetic backgrounds, including strains with altered prion protein (PrP) expression levels, they set up a subtractive analysis that drastically reduced biological and experimental noise and focused on sets of genes reflecting the disease process in common across the host genotypes and infectious agent strains. They defined the pathological/clinical end point as 'disease incubation time' from inoculation at age 5 weeks to advanced clinical impairment, ranging from 56 to 392 days. Genome-wide analysis of gene expression in whole brain homogenates was performed over 8–10 time points, with 1–4 week time intervals adjusted to the wide range of incubation times.

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