Northwestern University Physical Sciences-Oncology Center's (NU PS-OC) main focus is to probe the molecular basis of information flow within malignant cells. This center’s studies will highlight diverse characteristics of gene expression and storage. Moreover, these investigators postulate that in the cancerous state, the epigenome is significantly mutated. By merging experimental molecular and cellular biology with the physical sciences, these investigators will examine the regulation and expression of genes. In addition, they will explore the three-dimensional organization of the genome and the higher order chromatin structure using leading-edge physical techniques. Insight into chromatin structure modifications in malignant cells has the potential to expedite the development of tools for the early diagnosis of cancer. These investigators will also provide a foundation of basic understanding for how normal gene expression is calibrated and for how the epigenome as well as the proteosome are regulated. A clear understanding of these basic molecular functions should generate novel targets for cancer therapy.
Principal Investigator: Thomas V. O'Halloran, Ph.D.
Senior Scientific Investigator: Jonathan D. Licht, M.D.
Founding Principal Investigator: Jonathan Widom, Ph.D.
Collaborators: California Institute of Technology, Children's Memorial Hospital, University of Chicago, University of Illinois-Urbana, Weizmann Institute
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Thomas V. O’Halloran, Principal Investigator
Dr. O’Halloran is widely known for his interdisciplinary research program, which involves chemical synthesis, analytical chemistry, biochemistry, molecular biology and cell biology. In his role as Director of the Chemistry of Life Processes Institute, Professor O’Halloran administers and leads teams of interdisciplinary biomedical researchers. The Institute brings together researchers from the fields of chemistry, biology, physics, engineering, medicine, proteomics, nanobiotechnology, molecular therapeutics and biological molecular imaging. He also serves as the Associate Director for the Basic Sciences Research Division of the Robert H. Lurie Comprehensive Cancer Institute.
Dr. O'Halloran is the Morrison Professor in the Department of Chemistry and in the Department of Molecular Biosciences at Northwestern. His research interests focus on biological chemistry of inorganic elements and novel agents for treatment of infectious diseases and cancer.
Jonathan D. Licht, Senior Scientific Investigator
Dr. Licht is the Johanna Dobe Professor of Medicine and Chief of the Division of Hematology/Oncology and Associate Director for Clinical Sciences Research of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Dr. Licht, a graduate of Columbia University College of Physicians and Surgeons, trained in medical oncology and molecular biology at the Dana-Farber Cancer Institute of Harvard Medical School. On the faculty of the Mount Sinai School of Medicine for 15 years, he rose to the rank of Professor of Medicine and Associate Dean for Cancer Programs before his recruitment to Northwestern in 2006. Since that time he has built a robust basic research group within the Division of Hematology/ Oncology.
Dr. Licht is currently the Principal Investigator of a Leukemia and Lymphoma Society Specialized Center of Excellence grant, studying gene regulation mechanisms in hematological malignancy. He is a member of the Board of Scientific Councilors of the National Cancer Institute, is a Senior Editor of Clinical Cancer Research and serves on the editorial board of Oncogene. He also served as a Councilor of the American Society for Clinical Investigation and is a member of the Association of American Physicians.
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John Marko, Project Leader
A faculty member in both the WCAS Physics and Astronomy Department and Molecular Biosciences Department and affiliated with the Interdepartmental Biological Sciences Program (IBiS), Dr. Marko works on the application of statistical mechanics and polymer physics to biophysical problems, particularly micromechanical studies of DNA, DNA-protein interactions and chromosome structure and dynamics. His laboratory uses biophysical methods emphasizing micromanipulation of singe DNA molecules and single chromosomes. He also performs theoretical modeling related to these experimental studies.
Dr. Marko received his PhD from the Massachusetts Institute of Technology and came to Northwestern from the Physics Department at the University of Illinois at Chicago. He is a recipient of the NSF Faculty Early Career Development Award.
William Kath, Project Leader
William L. Kath is Professor of Engineering Sciences and Applied Mathematics in the McCormick School of Engineering and has an additional appointment in the Department of Neurobiology and Physiology in the Weinberg College of Arts and Sciences. During Fall 2010, he is a Washington Square Health Foundation Fellow in the Lurie Cancer Center. He is also a member of the Northwestern Institute on Complex Systems (serving from 2005-2010 as co-Director).
His current research focuses on mathematical and computational models of biological systems. He has also worked on methods to predict rare events in optical fiber communication systems.
Dr. Kath received his Ph.D. from the California Institute of Technology in 1981 and joined Northwestern University in 1984. His recognitions include a National Science Foundation Presidential Young Investigator Award (1985-1990), Fellow of the Optical Society of America (2007) and Fellow of the Society for Industrial and Applied Mathematics (2010).
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Project 1 - Information encoded in the sequence dependent mechanics of DNA:
Investigators seek to understand the rules that govern the propensity of DNA to bend and loop, both in vitro and in vivo, with an emphasis on the influence of DNA sequence and sequence length. The flexibility of DNA is critical to its ability to wrap around histone octamers to form nucleosomes and to form loops that bring into proximity transcription factors that are bound at non-contiguous sites. Deformations to the classical alpha helical structure formed by double stranded DNA accompany DNA bending, and seek to understand the physical chemistry of these deformations and how they influence the sequence dependence of nucleosome formation. An exciting finding is that distortions in helical structure can have regulatory significance.
Project 2 - DNA Sequence-Encoded Nucleosome Positioning and Gene Regulation:
Project 2 is employing a variety of technologies and mathematical approaches to gain a more quantitative and granular understanding of how nucleosome occupancy and histone modifications contribute to the transcriptional regulation and to its dysregulation in cancer. While the prevailing view is that nucleosomal DNA has reduced accessibility to transcription factors, this is probably too simplistic a view. Likewise, there is only a superficial understanding of the kinetics, dynamics, and biological effects of histone modifications, which occur in a huge variety of combinations.
Project 3 – DNA Information and Organization at Supranucleosomal Length Scales:
Project 3 seeks to uncover the connection between higher-order chromatin structure and gene regulation mechanisms relevant to cancer. An important effect of higher-order structure may be that origins of replication can be defined and regulated by chromatin structure, rather than by specific DNA sequence elements; changes in higher order structure in chromatin may appear in precancerous tissue, suggesting a hypothesis that optical detection of the “field effect” used in cancer diagnosis may follow from measurement of amounts and distribution of heterochromatin. This will allow understanding the basic chromosome organization changes associated with turning on malignancy, and then lead to use of those changes in establishment of new diagnostic tools.
Project 4 – Dynamic Nucleosome Signatures in Epigenetic Memory and Cancer Development:
Increasing evidence indicates that cancer results not only from changes in genetic information, but also from changes in epigenetic information, and recent theoretical analyses of epigenetic regulation in a model organism (yeast) show that ideas from the dynamical systems field may explain the stability of epigenetic states and the dynamics of spontaneous changes between them. This project will experimentally define the epigenetic changes resulting from the action of (1) a mutant kinase JAK2V617F, a causative factor in myeloproliferative disease; (2) a defined set of oncogenes that transform normal human cells to cancer cells (T antigen, ras, shRNA PP2a, telomerase); and (3) the changes in state of the MLH1 promoter that accompany gene silencing associated with promoter methylation, and reactivation that is induced by 5-aza-2'-deoxycytidine and is associated with DNA demethylation. We will use this information to develop quantitative predictive models of epigenetic inheritance and switching in these systems, based on a dynamical systems framework.
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Core 1 - The Deep Sequencing Core
Core Leader: Peter Kopp (Northwestern University)
The Deep Sequencing Core provides massively parallel DNA sequencing services using an ABI SOLiD (v3) instrument. A second parallel sequencing instrument, suitable for paired ends sequencing, will also be used. Experiments supported by this technology includes genomewide nucleosome mapping, mapping bound transcription factors genome-wide using chromatin-immunoprecipitation / sequencing (ChIP-seq), and gene expression profiling (RNA-seq).
Core 2 - The Bioinformatics Core
Core Leader: Ji-Ping Wang (Northwestern University)
The Bioinformatics Core provides advice and assistance in the analysis of genome-wide DNA sequence and microarray data, and in integrating different kinds of such data together to test hypotheses about genome structure and function. The mission of the Bioinformatics Core is to provide strong and timely bioinformatic support for all of the NU-PSOC projects by developing novel bioinformatic approaches and tools for the biological problems encountered in the Center's research. Operating within this broad framework, the Core will pursue two main goals: to promote and catalyze interdisciplinary research by providing a platform for interaction between computational scientists and biologists or cancer researchers; and to create training opportunities for postdoctoral fellows or graduate students.
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Video archive of seminars, workshops and symposia of the Northwestern PS-OC.
Press release highlighting a trio of publications that reveal important new methodological advances that have led to a new understanding of the forces governing the regulation of gene expression.
Media showcasing Prof. Vadim Backman's novel optics technologies aim at improving early detection of cancer.
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