Galagan Maps Molecular Circuitry behind a Persistent Disease
By Gina DiGravio, Boston Medical Center
M. tuberculosis bacteria. Associate Professor James Galagan (BME, Bioinformatics, Microbiology) is taking a systematic approach to pinpointing the genes and proteins in the TB bacterium that trigger disease. (Image courtesy of Centers for Disease Control and Prevention)
Associate Professor James Galagan
Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), can produce devastating infections of the lungs and other parts of the body. According the latest reports of the World Health Organization and the Centers for Disease Control, in 2011 there were about 8.7 million new TB cases worldwide causing an estimated 1.4 million deaths, and 10,500 new cases in the U.S. with recent TB outbreaks reported in Virginia, Los Angeles and South Carolina.
Now, in a study from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL), Associate Professor James Galagan (BME, Bioinformatics, Microbiology) and collaborators have generated a map of the cellular circuitry of M. tuberculosis. Published in the journal Nature, the study sheds new light on the bacterium’s ability to survive inactive in the human body for decades, resist treatment and trigger disease.
“We have generated the first large-scale experimental map of thousands of molecular interactions in the bacterium that enable it to cause disease,” said Galagan, associate director of Systems Biology at the NEIDL, who with Gary Schoolnik, professor of microbiology & immunology at Stanford University School of Medicine, led an international consortium of researchers including scientists from the Seattle Biomedical Research Institute, the Brigham and Women's Hospital, Metabolon Inc., Caprion Proteomics Inc. and the Max Planck Institute for Infection Biology. “Based on this map, we have developed the first computer models that will ultimately enable us to more easily study this challenging infectious organism and develop new drugs, therapeutics and diagnostics.”
The researchers examined the interactions of 50 transcription factors, which are proteins in cells that decide how the cell responds to its environment. They also mapped the molecular response of the bacterium to low oxygen, a condition that reflects the host environment within which the bacterium must survive. As they charted this previously unexplored territory, Galagan and his co-investigators made a number of surprising discoveries.
“We pinpointed many molecules, interactions and responses that appear important for the bacterium but that had been previously overlooked. These provide new avenues for combating this disease,” he said.
The study leveraged technologies and approaches developed for the Human Genome Project. In the next step, the researchers will apply these technologies to M. tuberculosis while it is residing in a macrophage, one of the body’s immune cells that the bacterium tends to inhabit, in order to enhance knowledge on how it is able to survive in the body for an extended amount of time.
This research, which expanded to the NEIDL in April 2012 after the lab was approved for Biosafety Level 2 (BSL-2) research, was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Department of Health and Human Services, the Paul G. Allen Family Foundation, the National Science Foundation Pre-doctoral Fellowship Program and the Burroughs Wellcome Fund Award for Translational Research.
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