Boston University Medical Campus
Pulmonary, Critical Care, and Allergy Medicine

Mission Statement:
Directed by Dr. Avrum Spira, the Bioinformatics and Systems Biology program at the Boston University Pulmonary Center consists of group of Pulmonologists and Bioinformaticians involved in translational research into lung biology and disease. The long terms goals of this program are to apply and stimulate the development of post-genomic technologies and computational tools for translational research into human disease and to train physician-scientists and graduate students who can apply these tools in a clinical setting.

Background:
With the complete sequence of the human and other genomes recently elucidated, we have witnessed an explosion of information and high-throughput tools that are profoundly altering biomedical research and the culture of science. The reference genomes combined with advances in the biotechnology sector have produced an exponential growth in the amount and types of data available regarding biological systems. These developments are altering the paradigm of biological research, from traditional studies of single genes or pathways to large scale studies that combine data-mining of high-throughout datasets (i.e. cDNA microarray experiments) for hypothesis generation with experimental work for validation. The reference human genome has also allowed us to rapidly characterize polymorphisms across the human population, and has also enabled molecular fingerprinting technologies that can identify the precursors and consequences of normal and pathological changes in gene and protein expression.

Driven by this large and rapidly increasing amount of data over the last several years, the discipline of Bioinformatics has emerged whose goal is to apply the techniques from computer science, such as data manipulation and pattern discovery techniques, to solve problems in molecular biology. The field of Bioinformatics has now begun to move beyond the genome-wide study of individual biological components (i.e. genes or proteins) to integration of interactions and relationships between various components of the biological system, to provide an understanding of the whole biological system (i.e.“Systems Biology”).

The Bioinformatics and Systems Biology Program strives to apply and develop computational tools that can be used to mine data from high-throughput translational research studies ongoing within the Pulmonary Center. This program combines expertise in designing and running genome-wide studies of gene and protein expression (using cDNA microarray and mass spectrometry) on clinical specimens with high-throughput data storage and analysis capabilities (see figure below). The scientists affiliated with this Program combine talents of molecular biologists with mathematicians, statisticians, epidemiologists and computer scientists. A number of the ongoing projects within the program are described below. This program along with the LUNG CANCER PROGRAM directed by Dr. Jerome Brody together form the Pulmonomics Lab at Boston University Medical Center.

Our program also serves to train Bioinformatics and Pathology graduate students and clinician- scientists in the application of these tools to clinical studies. In conjunction with the Dr. Charles DeLisi at the College of Engineering at BU, we have developed a Masters Program in Clinical Bioinformatics (MD track) whose goal is to train physicians who will be leaders in applying and stimulating the development of post-genomic technologies to clinical research and the practice of medicine. In addition, our program is closely affiliated with the Translational Bioinformatics Core of the newly formed Clinical and Translational Science Institute (BU-BRIDGE) at Boston University

Selected Ongoing Research Projects:

• The Airway Transcriptome: Developing Biomarkers for Lung Cancer and COPD: Developing Biomarkers for Lung Cancer and COPD: As one of the central projects within our program, the goal of this study is to profile gene expression changes occurring in intrathoracic (bronchial) and extrathoracic (buccal mucosa and nasal epithelium) airway epithelial cells in the setting of tobacco exposure and develop molecular biomarkers that can predict those smokers at risk for having or developing lung cancer and COPD. This study has defined the genome-wide impact of smoking and smoking cessation on bronchial airway epithelium (Spira et al. PNAS, 2004; Beane et al. Genome Biology. submitted) and has recently identified an airway signature that can serve as a highly sensitive and specific diagnostic in smokers with clinical suspicion of lung cancer (Spira et al. Nature Medicine. 2007; Beane et al. Cancer Prevention Research 2008). A large multicenter clinical trial will be performed to validate this early diagnostic biomarker for lung cancer. In collaboration with Drs. Andrea Bild (University of Utah) and Stephen Lam (University of British Colombia), this project has also begun to explore how the molecular “field of injury” in airway epithelium reflects information about the perturbation of specific oncogenic pathways within an individual, potentially allowing personalized genomic approaches to chemoprophylaxis and therapy.
• Mechanisms of regulation of airway epithelial gene expression: Our program has begun to explore genetic, epigenetic and post-transcriptional regulators of gene expression changes within airway epithelial cells. In collaboration with Dr. Douglas Bell at the NIEHS and Dr. Marc Lenburg in the Department of Genetics and Genomics at BUMC, we are linking gene expression profiles to SNPs in promoter regions of these genes via computational modeling and a novel high-throughput SNP platform. Dr. Frank Schembri and Sriram Sridhar are exploring the role of microRNAs in post-transcriptionaly regulating gene expression in these cells using microRNA arrays. We have also begun to link methylation of promoter regions to alterations in gene expression via whole-genome methylation arrays.
• Constructing Biological Networks: In collaboration with Dr. James Collins in the College of Engineering at BU, we are developing novel reverse engineering algorithms to reconstruct gene regulatory networks from airway microarray data in order to define molecular pathways that characterize smokers with lung cancer and COPD.
• Developing Non-Invasive Biomarkers of Tobacco Exposure for the NIH Genes and Environment Initiative. The program was recently awarded a U01 grant from the NIEHS to develop non-invasive biomarkers (using nasal and buccal epithelium) of host response to cigarette exposure. Biomarkers will be correlated with lung function and systemic markers of oxidant stress and inflammation to begin to understand the biological mechanism of the variation in response to tobacco smoke including those that relate to risk of developing COPD. These biomarkers will ultimately serve as noninvasive measures of the biological response to tobacco exposure that can be applied to large-scale population studies as part of the NIH/NIEHS Genes and Environment Initiative.
• Immunopathology of the Nasal Mucosa in Sarcoidosis: Together with Dr. Jeffrey Berman, we are studying gene expression profiles of nasal epithelium in the setting of sarcoidosis and their relationship to clinical outcome.
• Gene–expression profiles in mediastinal lymph nodes as predictors of lung cancer prognosis: Together with Dr. Hasmeena Kathuria and Dr. Ben Daly, we are exploring whole-genome expression profiles in paraffin-embedded lymph nodes from stage-1 lung cancer subjects and linking these profiles to survival post-resection.
• Constructing relational database for large-scale genotyping project within the Framingham Heart Study. We are working with investigators in the Framingham study to develop tools to manage and integrate results from ongoing genetic studies involving data from the 500K Affymetrix SNP array on over 9000 subjects

Expertise:
DNA microarrays
MicroRNA arrays
MALDI-TOF MS for high-throughput gene expression and methylation
Tandem Mass Spectometry for proteomic profiling
SNP arrays
Construction of relational databases
Reverse Engineering of Biological Networks

Principal Investigators:
Avrum Spira, MD; The Pulmonary Center
Jerome Brody, MD; The Pulmonary Center
Frank Schembri, MD; The Pulmonary Center
Gang Liu, PhD; The Pulmonary Center
Paola Sebastiani, PhD; School of Public Health, Boston University
Dan Brooks, ScD; School of Public Health, Boston University
Marc Lenburg, PhD; Department of Pathology
Marc Lenburg, PhD; Department of Genetics and Genomics
Martin Steffen, MD, PhD; Department of Genetics and Genomics
Marisa Ramirez, PhD; The Pulmonary Center
Hasmeena Kathuria, MD, The Pulmonary Center
Marty Joyce Brady, MD; The Pulmonary Center
George O’Connor, MD; The Pulmonary Center
Karen Schlauch, PhD; Department of Genetics and Genomics

Post-Doctoral Fellows:
Jennifer Beane, PhD; Pulmonary Fellow
Katrina Steiling, MD; Pulmonary Fellow
Christina Anderlind; Pulmonary Fellow

Graduate Students:
Adam Gustafson (PhD candidate, Bioinformatics)
Sriram Sridhar (PhD candidate, Pathology and Laboratory Medicine)
Catalina Perdomo (PhD candidate, Genetics and Genomics)
Xiaoling Zhang (PhD candidate, Bioinformatics)
Adam Gower (PhD candidate, Bioinformatics)
Julie Zeskind (PhD candidate, Bioinformatics)
John Brothers (PhD candidate, Bioinformatics)
Ayla Ergun (PhD candidate, Biomedical Engineering)

Study Coordinator:
Martine Dumas, MPH

Research Assistant:
Erika Langer

Collaborators (outside of BU medical center):
James Collins, PhD; College of Engineering, BU
Douglas Bell, PhD; National Institute of Environmental Health Sciences, NC
Joseph Keane, MD; Trinity College, Ireland
John Beamis, MD; Lahey Clinic, Burlington, MA
Bartolome Celli, MD, and Victor Pinto-Plata, MD; St. Elizabeth’s Hospital, Boston
Andrea Bild, PhD, University of Utah
Stephen Lam, MD, University of British Colombia
James Hogg, MD, University of British Colombia
Rafael Guerrero, PhD and David Sidransky, MD, John Hopkins School of Medicine
Pierre Massion, MD, Vanderbilt University
William Rom, MD, NYU
David Ulrich, Genehome Inc.

Links:
Pulmonomics lab
Lung Cancer Program

Selected Publications:
Beane J, Sebastiani P, Whitfield T, Steiling K, Lenburg M, Spira A. A Prediction Model for Lung Cancer Diagnosis that Integrates Clinical and Genomic Features. Cancer Prevention Research. 1: 56-64, 2008.

Sridhar S, Schembri F, Zeskind J, Shah V, Gustafson A, Steiling K, Liu G, Dumas Y, Zhang S, Brody J, Lenburg M, Spira A. Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium. BMC Genomics. 9:259, 2008.

Beane J, Sebastiani P, Liu G, Brody J, Lenburg M, Spira A. Reversible and Permanent Effects of Tobacco Smoke Exposure on Airway Epithelial Gene Expression. Genome Biology. 8: R201, 2007.

Millien G, Beane J, Lenburg M, Lu J, Spira A, Ramirez M. Characterization of the mid-foregut transcriptome identifies genes regulated during lung bud induction. Mechanisms of Development. 8:124-39, 2008.

Spira A, Beane J, Shah V, Steiling K, Liu G, Schembri F, Gilman S, Dumas Y, Calner P, Sebastiani P, Sridhar S, Beamis J, Lamb C, Keane J, Lenburg M, Brody J. Airway Epithelial Gene Expression in the Diagnostic Evaluation of Smokers with Suspect Lung Cancer. Nature Medicine. 13:361-6. 2007.

Zhang X, Liu G, Lenburg M, Spira A. Comparison of smoking-induced gene expression on Affymetrix exon and 3’ based expression arrays. Genome Informatics. 18:247-257, 2007.

Brody JS, Spira A. Inflammation, Lung Cancer and COPD. Proc Am Thorac Soc. 3:535-7. 2006.

Demeo D, Mariani T, Lange C, Srisuma S, Litonjua A, Celedón C, Lake S, Reilly J, Chapman H, Mecham B, Haley K, Sylvia J, Sparrow D, Spira A, Beane J, Pinto-Plata V, Speizer F, Shapiro S, Weiss S, Silverman E. The SERPINE2 gene is associated with Chronic Obstructive Pulmonary Disease. Am J Human Genetics. Am J Human Genetics. 78: 253-64, 2006.

Millien G, Spira A, Hinds A, Wang J, Williams M and Ramirez M. Alterations in gene expression in T1alpha null lung: a model of deficient alveolar sac development. BMC Developmental Biology 6:35. 2006.

Shah V., Sridhar S., Beane J., Brody J., Spira A. SIEGE: Smoking Induced Epithelial Gene Expression Database. Nucleic Acids Res. 33: D573-9. 2005.

Spira A*, Beane J*, Pinto-Plata V*, Kadar A, Liu G, Shah V, Celli B, Brody, J.S. Gene Expression Profiling of Human Lung Tissue from Smokers with Severe Emphysema. Am J Respir Cell Mol Biol. 31: 601-610. 2004. *contributed equally and should be considered co-first authors.

Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, Palma J, Brody J. Effects of Cigarette Smoke on the Human Airway Epithelial Cell Transcriptome. Proc Natl Acad Sci USA. 101:10143-8, 2004.

Spira, A, Beane J, Schembri F, Liu G, Yang X, Ding C, Gilman S, Cantor C, and Brody J. Noninvasive method for obtaining RNA from buccal mucosa epithelial cells for gene expression profiling. Biotechniques. 36:484-87, 2004.

Hoffman A, Awad T, Spira A, Palma J, Webster T, Wright G, Buckley J, Davis R, Hubbell E, Jones W, Tibshirani R, Tompkins R, Triche T, Xiao W ,West M, Warrington J. Expression profiling — best practices for data generation and interpretation in clinical trials. Nature Reviews Genetics. 5: 229-38, 2004.