It is anticipated that the ISM will have both basic and translational research programs in areas such as:

• Epigenomics
• Genomics
• Systems Biology
• Chromosomal Biology
• Computational Biology

Multi-year projections estimate that the ISM will grow to approximately 20 Principle Investigators (PIs) by Year 3. Each program will consist of a relatively equivalent mix of junior, senior, and star faculty to achieve sustainability of the research at the ISM. Many of the faculty members are expected to receive joint appointments between the ISM and partner affiliates. It is anticipated that these PIs will be recruited from affiliate organizations as well as from outside the region. Each PI is anticipated to have a team that consists, on average, of 4 to 10 positions for technical staff, Post Doctoral trainees, and Graduate Research Assistants, some of whom are expected to arrive with the PI while the balance will be hired as the programs ramp up over a few years. These research resources will achieve a critical mass designed to advance discovery and its translation to the patient in Systems Medicine, train a pipeline of young researchers, and secure a strong competitive research position for the ISM and its partners.

1. Epigenomics Program
As previously mentioned, Epigenomics (also known as Epigenetics) is a growing field of study that provides an opportunity to explain the role of regional differences as well as environmental factors in disease status. The ISM will pursue several basic science and translational research ventures within the field of Epigenomics, which may specifically include:

• Epigenome Map: The human epigenome map, similar to the DNA sequence map, is needed and the ISM can take a lead role in the growing interest to develop the map.

• Epigenomic Detection Technology: Current biochemical procedures for epigenomic detection are not suitable for large scale or high throughput; therefore, new technology, involving array technology, is needed.

• Epigenomic Diagnostics and Therapeutic Technology: Develop novel technology to apply to new diagnostics and therapeutics identified.

• Epigenomic Analysis of Disease: Correlate changes to the epigenome to the development of disease.

• Environmental Impact on Epigenome and Disease: Investigate the environmental toxicology of changes in the epigenome and correlate to the development of disease

• Develop Epigenomic Diagnostics and Therapeutics for different disease states: Identify predictive and prognostic markers as well as therapeutic targets and treatments for different disease states.

In December 2005 a group of 40 international scientists publicly proposed a U.S. Human Epigenome Project to complement a European project of the same name launched in 2003. Group member Andrew Feinberg, geneticist at the Johns Hopkins University School of Medicine, says, Were hoping to see how this idea takes hold. There is this ocean of information that is largely unexplored.

The goal of the U.S. project will be to comprehensively map methylation and histone modifications the main classes of Epigenomic modifications in a diverse set of normal tissues. These epigenomes would then serve as a reference for comparison with diseased tissues, revealing Epigenomic causes of disease. Project organizers are now compiling a detailed proposal, with budget estimates and a timeline. Although both the U.S. and European projects ultimately aim to map all genes, the U.S. effort will look at different tissue and cell types than the European effort, and will also look at model organisms like yeast and the fly. The two groups are already working closely together in planning their projects to avoid redundancies, and this cooperation will likely continue.

Understanding cancer would be one long-term goal for the U.S. project, but Epigenomics, changes in gene expression heritable from cell to daughter cell without changes in DNA sequence, transcends any one disease. It has profound implications in aging, neurological disorders, and child development, says Peter Jones, another group member and director of the Norris Comprehensive Cancer Center at the University of Southern California. Jones and his colleagues argue that the importance of Epigenomics in human disease, together with the maturing of technologies for mapping Epigenomic changes, make a human epigenome project both critical and feasible.

Epigenomics, says cancer biologist Jean-Pierre Issa of The University of Texas M.D. Anderson Cancer Center, could prove more important than genetics for understanding environmental causes of disease. Cancer, atherosclerosis, Alzheimers disease [are all] acquired diseases where the environment very likely plays an important role, he points out. And theres much more potential for the epigenome to be affected than the genome itself. Its just more fluid and easier to be the culprit.

- Environmental Health Perspectives: Volume 114, Number 3, March 2006.

2. Genomics Program
Genomics is the study of an organism's genetic material, which delineates the blueprint for all proteins to be created by a living organism. The ISM will conduct genomic analysis of disease to correlate changes in the genome to the development of disease. A translational research goal of the ISM, applying both Genomics and Systems Biology, will be to identify predictive and prognostic markers of different disease states using genetics as a diagnosis tool, as shown in the graphic at right.

3. Systems Biology Program
The Systems Biology research program will focus on the generation, interpretation, and integration of data specific to the areas of biology, mathematics, computer science, engineering, and physics as they pertain to biomedical research. Systems Biology seeks to further understand the interrelated networks of genomic expression into proteins within the body. Specifically, an understanding of these networks will lead to the ability to predict disease and develop proactive treatments.

4. Chromosomal Biology Program
The aim of the Chromosomal Biology program is to elucidate the chromosomal basis of genetic disease. Chromosomes are linear aggregates of DNA and protein-containing bodies that carry hereditary information. In general, Chromosomal Biology addresses the course of events that occur when cells grow and divide into those found throughout most of the body (known as somatic cells) as well as those found only in the reproductive organs (known as gametes or sex cells). Phenomena that occur on the chromosomal level are considered to be among the main mechanisms by which epigenomic information is generated. In essence, a major advantage of using this mechanism to assess disease states through Epigenomics is the opportunity to discover ways to safely and effectively influence the manner in which genomic DNA is expressed without tampering with the DNA sequence directly. For example, future studies in the area of Chromosomal Biology, as it pertains to Epigenomics, may elucidate diagnostic methodologies for diseases such as cancer or multiple sclerosis. The figure on the previous page offers a graphical explanation of the role of chromosomal biology in Systems Medicine.

5. Computational Biology Program
The establishment of a solid Computational Biology component is essential to the ISM's ability to efficiently and accurately accelerate progress in the translation of biomedical discoveries. The Computational Biology Program will employ computational bioinformatics and prediction analysis to correlate the Epigenome, the genome sequence, and expression profiles for predictive systems medicine purposes. The Computational Biology program will require multidisciplinary expertise from multiple fields, some not traditionally affiliated with life sciences and medicine such as engineering, mathematics, and statistics. Much of this expertise is expected to be obtained through affiliations with academic and research institutions, complementing the skills of the anticipated investigators within the Computational Biology Program.