New Center Wields Genome Data to Battle Bugs
The bacterium Pseudomonas aeruginosa can be found almost everywhere: in soil, in water, inside and outside plants and animals. But there is one place Stephen Lory does not want to see P. aeruginosain the lungs of cystic fibrosis patients.
Stephen Lory is director of the new Center for Genomic Applications and Therapeutics whose first mission is to develop therapeutics against Pseudomonas aeruginosa in cystic fibrosis patients.
Lory, professor of microbiology and molecular genetics, arrived in late August from the University of Washington, Seattle, to become director of that department's new Center for Genomic Applications and Therapeutics (known by the genomically apt acronym CGAT). The same week, Nature published the P. aeruginosa genomethe largest bacterial genome to date, with six million base pairs and approximately 5,800 genessequenced through a Cystic Fibrosis Foundation project by a University of Washington team led by Maynard Olson and Lory. Together, those two events may mark the beginning of a new era in cystic fibrosis (CF) research.
Department chair John Mekalanos envisions CGAT as eventually taking on a wide variety of projects made possible by progress in bacterial and human genomics. But he describes the center's first mission as highly focused: to "apply state-of-the-art technology in genetics, chemistry, and immunology to develop therapeutic approaches toward the complete eradication of Pseudomonas aeruginosa as a pathogen of patients with cystic fibrosis.
"I am delighted that we successfully recruited Steve Lory to direct CGAT," said Mekalanos. "He has been a tremendous contributor to the field of bacterial pathogenesis. Steve has worked on this difficult organism for most of his career and consequently is a superb choice to lead CGAT in this effort."
The Bacterium's TollThe bacterium almost inevitably causes chronic and often fatal lung infections in CF patients. These infections, and the inflammatory overreactions to them, are the most important cause of morbidity and mortality in the disease. The average life expectancy of CF patients is now about 30 years. But according to Lory, "If we can eradicate P. aeruginosa, with reasonable medical intervention CF patients could potentially live to old age just like anybody else."
New weapons to battle the bug would help others, too. P. aeruginosa does not infect healthy people but is notorious for its opportunistic attacks on hospitalized patients. Those most vulnerable include patients with severe burns or wounds; immunosuppressed cancer, AIDS, and transplant patients; and catheterized patients whose urinary tracts become infected. Its natural resistance to many antibioticsthe result of evolutionary adaptations needed to survive in diverse environmentsmakes it an especially dreaded pathogen.
Moreover, said Lory, while CGAT's research will initially aim at just one organism, its findings are likely to have wider application.
"With the genomic approach, when we identify targets for antibiotics, similar targets may be found in other bacteria as well," he said. "There's a reasonable chance that a compound that works on Pseudomonas will also work on other organisms."
Battle PlansA native of the former Czechoslovakia, Lory has made several coast-to-coast hops in the past two decades. After completing both BA and PhD degrees at UCLA, he worked as a research fellow in the Bacterial Physiology Unit at HMS from 1980 to 1984. He then joined the University of Washington microbiology faculty, where he remained until returning to HMS. His research has aimed at understanding the molecular pathogenesis of Gram-negative bacterial infections, including mechanisms of colonization, persistence, and resistance to host defenses. In recent years he has focused on the regulation of expression of virulence genes in P. aeruginosa, developing a genetic selection system to identify genes that are induced or repressed during infection.
The genome sequencing allowed Lory to develop microarray, or DNA chip, technology that makes it possible to analyze expression of every gene in the bacterium simultaneously. At UW he also applied to P. aeruginosa a technique called IVET (in vivo expression technology ) that was developed in the Mekalanos lab.
Research under way at HMS complements Lory's work in a way that is ideal for "taking it to the next stage," he said. For example, CGAT will collaborate closely with the Institute for Chemistry and Cell Biology to discover small molecule inhibitors of essential bacterial gene products. These inhibitors will provide new tools for understanding the 30 to 50 percent of bacterial genes that have no known function.
"The ICCB is one of a kind in the world," Lory said. "I'm very lucky to be here and to have them interested in my workthat was a big attraction for me."
Lory also looks forward to collaborations with HMS researchers who are already working on P. aeruginosa. They include Frederick Ausubel and Laurence Rahme at Massachusetts General Hospital, Gerald Pier of Brigham and Women's Hospital, Craig Gerard and colleagues at the Ina Sue Perlmutter Laboratory for Cystic Fibrosis Research at Children's Hospital (see Asthma,), as well as clinical researchers at Children's, which is one of seven therapeutics development centers sponsored by the Cystic Fibrosis Foundation to help bring basic discoveries to the clinic.
Over time, Mekalanos said, "CGAT will assemble a highly focused group of faculty and staff to mine microbial genomes for important medical applications, including the identification of targets for antibiotics, protective antigens, and other interesting therapeutics.
"The beautiful thing about establishing an effort like CGAT will be the cross-fertilization in other fields," he added. "For example, the center hopes to also fuel functional genomic efforts in the fields of virology and parasitology and provide a think-tank for postgenomic efforts in other fields such as proteomics and immunology."
The Cystic Fibrosis Foundation is providing CGAT's first external funding.
"Steve Lory has been a great friend of the CF Foundation over the years," said Robert J. Beall, the foundation's president and CEO. "We are delighted to be able to continue our support of his work."