Tuberculosis: Novel Therapies through Knowledge of the Genetics of the Causative Agent
While many Americans do not think of tuberculosis as a potential threat, each year this highly infectious airborne illness strikes more than 9 million people and causes close to 2 million deaths worldwide. Over 90% of new tuberculosis cases occur in developing countries throughout Africa and Asia, but the mobility of populations increases the likelihood of the disease spreading elsewhere. Drug-resistant strains of Mycobacterium tuberculosis are increasingly more prevalent, so continue to present a challenge.
More than 10 years have passed since the sequence of the M. tuberculosis genome was published, and the accumulated knowledge since then, together with recent use of innovative genetic techniques, has shifted the emphasis in TB drug discovery from empirical approaches to hypothesis-driven processes. These new processes can accelerate identification and validation of drug targets, unveil resistance mechanisms, and present new compound screening strategies and drug development pathways.
On April 6, 2010, academic researchers, public health professionals, and pharmaceutical industry scientists gathered at the New York Academy of Sciences for the symposium "Tuberculosis: Novel Therapies through Knowledge of the Genetics of the Causative Agent," to discuss how their knowledge of the complete M. tuberculosis genome sequence is being utilized to develop new TB drugs. The symposium highlighted recent advances in these areas and provided deeper insights, enabled by genetic tools, into the pathophysiology of the disease. Five outstanding speakers shared their research and painted the 'bigger picture' of the current state of TB drug discovery.
William Jacobs, from Albert Einstein College of Medicine, provided an excellent overview of the genetic strategies currently being used to counter the pathogen; then Christopher Sassetti, from the University of Massachusetts Medical School, gave the audience his insights into the 'eating and sleeping habits' of the bacteria, which could be utilized to improve current therapies. Dirk Schnappinger from Weill Cornell Medical College shared some recent pre-publication data exclusively with the New York audience on how to turn on and turn off M. tuberculosis genes in vivo, and then Helen Boshoff from the NIH discussed high-throughput screening technologies and hardware to identify potentially novel pathways for drug discovery. To conclude the symposium, Carl Nathan from Weill Cornell Medical College discussed the biochemistry behind the pathogen's persistence in vivo and possible ways to discover drugs aimed at such mechanisms.
Use the tabs above to find the multimedia from this event.
This event is part of the Dr. Paul Janssen Memorial Series at the New York Academy of Sciences.
For a complete list of sponsors, please click the Sponsorship tab.
Helena Boshoff, PhD
Helena I.M. Boshoff received both her BSc and MSc degrees in biochemistry at the University of Pretoria in South Africa. She continued graduate studies at the University of Witwatersrand, also in South Africa, where she received a PhD in molecular biology in 2000. She then conducted research on tuberculosis as a postdoctoral fellow in the Tuberculosis Research Section of the Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases at the NIH from 2001 until 2005.
From 2006 to 2008, she was a research fellow in the Tuberculosis Research Section. Since 2008, she has been a staff scientist and leads the biology section of the Tuberculosis Research Section, of which Clifton E. Barry III is chair. The Tuberculosis Research Section comprises a multidisciplinary group of research scientists including biologists, chemists, and clinical researchers who focus on understanding the scientific issues that facilitate the development of drugs that will improve chemotherapy of tuberculosis globally.
Boshoff's research interests include the identification and validation of drug targets in Mycobacterium tuberculosis, the etiologic agent of the disease, as well as mechanisms that give rise to drug resistance in this pathogen. Boshoff is the co-author of numerous articles in peer-reviewed publications and serves on the editorial board of the journals Tuberculosis and Drugs of the Future.
William R. Jacobs Jr., PhD
William Jacobs, by initiating work with mycobacteriophages, has developed novel genetic approaches to make mutations and transfer genes in Mycobacterium tuberculosis. With these tools, he has identified drug targets and novel virulence factors of M. tuberculosis, many of which are enzymes or products of complex lipid metabolism. These complex lipids are unique among bacterial pathogens and likely to contribute significantly to the pathogenic property of mycobacteria. His lab uses this knowledge to develop novel chemotherapies, vaccines, and diagnostic tests to treat tuberculosis.
Carl Nathan, MD
Carl Nathan is R.A. Rees Pritchett Professor and chairman of the Department of Microbiology and Immunology at Weill Cornell Medical College and co-chair of the Program in Immunology and Microbial Pathogenesis at Weill Graduate School of Medical Sciences of Cornell University. After graduation from Harvard College and Harvard Medical School, he trained in internal medicine and oncology at Massachusetts General Hospital, the National Cancer Institute and Yale before joining the faculty of the Rockefeller University from 1977 to1986. He has been at Weill Cornell Medical College since 1986, where he has served as founding director of the Tri-Institutional MD–PhD Program, senior associate dean for research and acting dean. A member of the Institute of Medicine of the National Academies of Sciences and a Fellow of the American Academy of Microbiology, Nathan serves as associate scientific director of the Cancer Research Institute, a Trustee of the Hospital for Special Surgery, and since 1988, an editor of the Journal of Experimental Medicine. He received the Robert Koch Prize in 2009 for his work on host defense against infection.
Over four decades Nathan established that lymphocyte products activate macrophages, that interferon-gamma is a major macrophage activating factor in mice and humans, and that mechanisms of macrophage antimicrobial activity include induction of the respiratory burst and inducible nitric oxide synthase (iNOS). Although iNOS helps the host control Mycobacterium tuberculosis, Mtb resists sterilization by host immunity. The biochemical basis of Mtb's persistence is the lab's present focus. Genetic and chemical screens have identified enzymes that Mtb requires to survive during non-replicative persistence, including the proteasome, a serine protease that controls intrabacterial pH, and components of pyruvate dehydrogenase and nucleotide excision repair, along with inhibitors of each.
Christopher Sassetti, PhD
Christopher Sassetti is an assistant professor of Molecular Genetics and Microbiology and the University of Massachusetts Medical School and an early career scientist of the Howard Hughes Medical Institute. After receiving his PhD in Immunology from the University of California San Francisco, he pursued his postdoctoral training in bacterial genetics at the Harvard School of Public Health. He joined the faculty at the University of Massachusetts in 2004. Sassetti's research focuses on the application of high-throughput genetic approaches to understand the how Mycobacterium tuberculosis adapts to the host environment.
Dirk Schnappinger, PhD
Dirk Schnappinger received his PhD from the Friedrich-Alexander University of Erlangen–Nürnberg, Germany in 1998. After his graduate work on protein engineering, Schnappinger began to study the human pathogen Mycobacterium tuberculosis, first at the University of California, Berkeley, and then at Stanford University. In 2001 he founded his own research group at the Weill Cornell Medical College. His work focuses on the development of genetic tools and the analysis of essential genes of M. tuberculosis.