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INTERNATIONAL MEDICINE Armenise Symposium 2002: Structural Biologists Reveal Struggle Between Pathogens and Their HostsTourists flock to the Virgin Islands to enjoy cloudless skies and blue waters, lilting music and musical speech, the easy pleasures of a seemingly carefree place. Although biologists enjoy the Caribbean as much as anyone else, presentations at the sixth annual symposium of the Giovanni Armenise-Harvard Foundation, held in the U.S. Virgin Islands, reminded them that paradise has a darker side. Only in sub-Saharan Africa is HIV spreading more rapidly than in this region, malaria and tuberculosis are endemic here, and children die routinely of diseases that could be prevented by immunization. "Structural Biology and Microbial Pathogenesis and the Host Response" gave 22 invited lecturers and an equal number of poster presenters a forum for discussing how X-ray crystallography and other structural studies illuminate the invisible struggle that rages between pathogens and their hosts. These are high-stakes battles, with infectious diseases accounting for one in three deaths worldwide and destroying about 15 percent of all agricultural crops. Some speakers focused on scourges of perennial interest, including cholera, malaria, tuberculosis, AIDS, and tetanus; others discussed possible defenses against anthrax, an old disease given new prominence by bioterrorism. Nearly 80 Armenise-sponsored researchers participated in the symposium, held June 27 to 29 on St. Thomas. Antigen ScanAlthough the foundation's commitment to basic science was clear, many speakers emphasized the urgency of translating basic discoveries into life-saving treatments and vaccines. Keynote speaker Rino Rappuoli set the tone, describing how genome sequencing and information technology have accelerated vaccine development at Chiron SpA, located in Siena, Italy, where he is vice president for vaccine research. Using a computer program to scan the genome of group B meningococcus, Chiron scientists needed only 18 months to identify 29 antigens that stimulated desirable immune responses in animals, and these have been incorporated into an experimental vaccine now undergoing phase I human testing. In contrast, vaccinologists using old-fashioned techniques had spent 40 years identifying fewer than 20 group B meningococcus antigens and none provided total protection in clinical trials.Armenise investigators also are using genome-based approaches to vaccine development. Having sequenced a classical strain of cholera bacteria two years ago, John Mekalanos used that information to identify genes unique to a newer strain that is causing today's cholera pandemic. Functional studies of these genes, which are now under way, will fuel the development of treatments, vaccines, and environmental controls as well, predicted Mekalanos, the Adele Lehman professor of microbiology and molecular genetics and head of that department at HMS. A Better Anthrax VaccineSince last fall, there has been tremendous demand for a new anthrax vaccine that is safer and more effective than the existing product. The availability of the Bacillus anthracis genome enabled Giuseppe Zanotti, of the University of Padua in Italy, to find two genes encoding essential iron-storing proteins called ferritins, which might be useful antigens in a second-generation anthrax vaccine.The endless resourcefulness of pathogens was also a recurring theme. TB's notorious ability to develop drug resistance may arise from the activation of more than 170 genes late in tuberculosis infection, according to a report from Eric Rubin, assistant professor of immunology and infectious diseases at HSPH. Having so many genes in play gives the bacterium many options when it is threatened, said Rubin, who used large-scale mutagenesis and microarrays to identify genes turned on as TB progresses. The urgency of understanding drug resistance was underlined by Dyann Wirth, who noted that the malaria parasite took 16 years to develop strains resistant to chloroquine, the first pharmaceutical used against it, but only 6 months to begin exhibiting resistance to the newest drug on the market. The sequence for this parasite is nearly complete, and soon researchers can use genomics to discover all the genes important for resistance, according to Wirth, HSPH professor of tropical health. Several speakers addressed nature's role as a factory. As vancomycin resistance becomes more of a problem in clinical medicine, the solution may be to analyze how this powerful antibiotic's original manufacturer, a bacterium, put it together in the first place. Once nature's assembly line is better understood, it may be possible to accelerate the making of new and improved antimicrobial drugs, said Christopher T. Walsh, HMS professor of biological chemistry and molecular pharmacology. The intracellular factorylike operation of reoviruses was explored by virologist Max Nibert, HMS associate professor of microbiology and molecular genetics. Infectious diseases are a threat to the world's food supply as well as its people, and structural and signal transduction studies are yielding promising information about how to fight back. Researchers from the University of Rome "La Sapienza," HMS, and the University of California presented their latest findings about host-pathogen interactions in plants. HMS professor of genetics Frederick Ausubel (see Focus, May 3, 2002) gathered together many threads in the final lecture of the symposium, summarizing evidence that innate immunity in creatures as diverse as plants, nematodes, and people relies on some of the same ancient and highly conserved cellular pathways. --Patricia Thomas |
