The Hood group is integrating biology, technology and computation to create a predictive, personalized, preventive and participatory approach to medicine. This P4 Medicine will use a systems or holistic approach and new computational and mathematical tools to analyze the enormous amounts of molecular, cellular, phenotypic and medical data that now can be generated for each individual. By viewing medicine as an informational science, P4 medicine will draw on an understanding of the networks underlying health and disease. The goals are to treat and prevent disease by identifying perturbations in biological networks, and countering those perturbations through therapeutic intervention. Furthermore, a systems approach to biology will create knowledge with far-reaching implications for agriculture, energy production, environmental protection, and many other human activities.

The Hood group is developing strategies, technologies and knowledge that will lead to medicine that is predictive, personalized, preventive and participatory -- P4 Medicine. The premise of their work is that diseases result from perturbations of biological networks. These perturbations may arise from biological changes, such as mutations in the digital information of the genome, or from environmental influences, such as toxins or bacteria. These disease-perturbed networks both cause and reflect the progression of a disease. Thus, diseases can be diagnosed, treated and prevented by understanding and intervening in the networks that underlie health and illness.

• It has pioneered a new approach to the identification of disease genes through the complete genome sequencing of families affected by particular diseases. Use of pedigree information makes it possible to correct a significant fraction of DNA sequencing errors, identify rare genetic variants (some of which contribute to diseases) and reduce the search space for disease genes.

• It is establishing the computational infrastructure needed to analyze the thousands and eventually millions of human genome sequences that will become available over the next ten years. These computational tools will enable large-scale comparative analyses of human genomes and their attendant molecular, cellular and phenotypic data.

• It is supporting a human proteome project that will parallel the human genome project. Using selected reaction monitoring (SRM) mass spectrometry, it has created targeted assays for virtually all human proteins, which opens up fascinating opportunities for identifying blood and tissue biomarkers.

• It is developing clinical assays that use genomic, proteomic and cellular analyses, including the use of induced pluripotent stem (iPS) cells, to explore development and to stratify disease. Through collaborations with the non-profit P4 Medicine Institute and Ohio State Medical School, these assays are being used to improve health in two pilot projects involving wellness and heart failure.

• A surface plasmon resonance instrument capable of making 1,000 measurements at a time to screen for effective antibodies and analyze other protein/protein interactions.

• A Nanostring instrument designed for the digital counting of RNA and miRNA molecules now being used to conduct highly sensitive protein assays. We are also exploring the use of this instrument to develop highly sensitive Eliza protein assays.

• A Fluidigm microfluidic array platform that will be used to quantify mRNAs and miRNAs in various single-cell studies.

Prion Disease
Studies in the Hood lab of neural degeneration in mice illustrate the power of the systems approach to disease. Members of the Hood team injected infectious prions -- proteins that induce disease by causing other prion proteins to assume new configurations -- into the brains of inbred mice. They then gathered data about brain gene expression as the disease progressed. Using microarrays, they compared patterns of gene expression in the diseased animals to those in normal animals at ten or more time points during the disease progression to identify differentially expressed genes (DEGs). They also looked at gene expression levels in eight different combinations of mouse-and-prion strains to eliminate by subtractive procedures biological "noise" unrelated to the disease. In this way, they reduced 7,400 DEGs identified in the original screen to 333 DEGs that encoded the core prion neurodegenerative response.

• In the first application of this approach the group sequenced the genomes of a family of four harboring an unknown gene with recessive inheritance causing Miller syndrome (Roach et al., 2010). No previously existing tools could be adapted to this challenge in high-throughput data analysis, so a computational workflow was developed in tandem with data analysis. Key innovations included being able to detect genotyping errors and inheritance state analys is. These encompass the filters and integrators mentioned above. The combination of highly accurate sequence data and precise pedigree analysis allowed the previously difficult feat of identifying the defective gene in a recessive disorder from only a single family of four (for Miller syndrome, this is DHODH).

• Now the group is using complete genome sequencing of families to identify variants in genes that interact with the primary defective gene (i.e., genetic modifiers) of the neurodegenerative disorder, Huntington's disease. Indeed, we are now analyzing 65 complete genome sequences from members of Huntington's Disease-affected families. Future studies will tackle even more complex, multigenic disorders such as Alzheimer's and Parkinson's disease, after appropriate disease stratification into their distinct types. In parallel with these specific disease studies, the group continues to develop and refine the computational tools needed for large-scale comparative analyses of human genomes, and the eventual utilization of whole genome sequence analysis in the clinic.