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Basic Research on Bacteria The Essential Frontier Report on the American Society for Microbiology and National Institutes of Health Workshop on Basic Bacterial Research The National Institutes of Health (NIH) The Nationʼs Medical Research Agency, the NIH includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov The American Society for Microbiology (ASM) The ASM is the largest single life science society, composed of over 42,000 scientists and health professionals. The ASM's mission is to promote research and research training in the microbiological sciences and to assist communication between scientists, policy makers and the public to improve health, economic well-being and the environment. The ASM and its members work to identify and support research efforts that can address health and environmental problems. February 2007 Cover and Interior Bacteria Images Staphylococcus aureus—coccus prokaryote (MRSA bacterium) Mycobacterium tuberculosis—rod prokaryote (bacterium) E. coli (Escherichia coli)—dividing, hemorrhagic 0157:H7 strain. © Dennis Kunkel Microscopy www.denniskunkel.com F Introduction or many years the American Society for Microbiology (ASM) has been concerned about the need for increasing basic research in bacteriology. This concern is based upon several premises, including: 1 the widespread perception that an adequate number of researchers in the U.S. in fields such as bacterial physiology and genetics are not being trained, 2 the importance of basic knowledge of bacterial physiology and genetics in the biotechnology industry and in applications including pathogenesis and biodefense, 3 the growing understanding of the impact of bacteria on human health, and on the development of chronic diseases. To address these questions, the ASM and National Institutes of Health (NIH) jointly sponsored a workshop on Basic Research in Bacteriology that was convened November 3-4, 2005 on the NIH campus in Bethesda, Maryland. T Approach he ASM-NIH workshop focused on scientific gaps and opportunities for research on bacteria. In order to stimulate creative, goal-oriented interactions, the meeting integrated focused discussions within smaller working groups and overarching sessions with entire group participation. Participants in the two-day workshop included scientists with a variety of research expertise, representatives of industry, and representatives of federal agencies. Following the meeting, the groupʼs Steering Committee prepared this summary of the discussions and recommendations to guide future research. Goal: The workshop participants focused on the following discussion areas: • What are the gaps in our knowledge, methodologies, and information access that must be addressed? What strategies would address these gaps? • How has microbiological research at the basic and applied levels been changed by technological advances (e.g., genomics, imaging, and computation)? What new opportunities have been revealed? • How have these technological advances altered the perception of what problems are interesting and important? What are the benefits and drawbacks to these changes? • What factors have changed the marketplace for microbiologists over the years and how? Is this picture changing again? What are the roles of the research institutions in these shifts and how might they be influenced in the future? What are the roles of the microbiological societies in future shifts? What roles might the private and public funding agencies play? • What are the developments on the horizon that will affect microbiological research in the next five years? Basic Research on Bacteria The Essential Frontier 1 B Overview acteria and their phages are the oldest and most abundant life forms on the planet. Bacteria have co-evolved with us and are beneficial for human health. There are over 10 times more bacteria in our bodies than there are human cells, and this natural microbiota is essential for proper development, nutrition, and resistance to disease. However, we also live in an environment replete with bacteria that can cause a wide variety of human diseases with bacterial infections responsible for 25 percent of human deaths globally, a number predicted to increase dramatically with the growing crisis of antibiotic resistance. We understand very little about the interactions between bacteria and the environment that influence the delicate ecological equilibrium between humans and microbes and thereby determine the balance between health and disease. In addition to the bacteria that are in or on the human body, bacteria influence humans in many other ways. Bacteria are the dominant occupant and architect of our entire biosphere. Bacteria sustain the metabolic cycles that are essential for all life on earth. Bacterial metabolism sculpts our physical environment as well. Because they are ubiquitous and have such diverse metabolic capabilities, bacteria influence essentially all disciplines of science, including fields such as evolutionary biology, ecology, immunology, cell and developmental biology, psychology, geology, chemistry, physics, climatology, computer science, and engineering. Bacteria are also instrumental for understanding fundamental life processes that are required by all organisms, including central metabolism, replication, transcription, translation, protein targeting, assembly and structure of macromolecular complexes, protein folding, stress responses, error correction mechanisms, signal transduction, and developmental programs. These processes are more easily characterized in model bacteria and their phages than in other organisms because microbes provide such tractable experimental systems. The large repertoire of genetic and biochemical tools and data that have been acquired from basic research on bacteria is crucial for dissecting the complex metabolic and regulatory networks that control these processes. This provides a launching point for understanding the enormous diversity in the bacterial world and facilitates the understanding of these processes in eukaryotes. 2 Despite the broad impact of this field, basic research on bacteria is at a crossroads. The research community perceives that public funding for most areas of basic research, including bacteriology, has leveled off and that increased resources are being focused on infectious disease research prompted in part by biodefense concerns. Coupled to this, large multi-investigator projects have emerged as an alternative to single investigator R01-type research projects. These developments raise the questions: What is the relative value of continued investment in basic research on bacteria, and is there a disproportionate emphasis on large scientific consortia at the expense of research by smaller groups? R Evolving Priorities esearch on bacteria and their phages has led to many fundamental scientific discoveries. Initial support for this research was justified in part because of the role of bacteria in causing disease. With the advent of effective antibiotics it seemed like the war on microbes had been won. Hence, for several decades health-related research shifted to topics like cancer, heart disease, and genetic diseases. Moreover, developments in molecular biology arising from research on bacteria made it possible to study many basic biological processes in mammalian cells, eliminating the argument that bacterial model systems were the only doorway to eukaryotic molecular biology. Meanwhile, the microbes demonstrated how rapidly they could evolve new traits. Microbial resistance to antibiotics developed faster than new antibiotics could be developed, and the resistance spread throughout the microbial world. The global expansion of food distribution networks facilitated the rapid distribution of microbial pathogens. Simultaneously, emerging microbial pathogens filled new ecological niches, such as indwelling medical devices and the growing population of humans who are immunocompromised due to primary infections (including HIV) or due to therapies used to treat chronic diseases. Furthermore, recent discoveries have demonstrated that some diseases (including ulcers, certain types of cancer, heart disease, etc.) that were previously believed to be caused by a genetic predisposition or exposure to environmental toxins are actually caused by microbes. This microbial offensive has summoned a renewed counter-attack on microbial pathogens. Meanwhile, new tools have become available that make it possible to dissect the molecular basis of pathogenesis both from the microbial and host perspectives. Recently, having the complete DNA sequences of bacterial pathogens has provided valuable insights into how microbial pathogens evolve and the extent of gene transfer between pathogens. These advances have revealed new ways to control infection, including the identification of novel targets for antimicrobials and novel approaches for vaccine development. The value of basic research on bacteria has extended well beyond infectious diseases. Research on bacteria led to the elucidation of important concepts of molecular biology, allowing developments in biotechnology that have yielded tremendous benefits to many other aspects of human health and well-being as well as providing new tools that have facilitated our understanding of pathogenesis. With the advent of new tools that allowed us to extend beyond pure culture studies to identify bacteria in complex communities in the environment, it became clear that bacteria have many roles in human health that were previously unknown. These discoveries have opened important new opportunities for research on bacteria. Although these new technologies allow the rapid accumulation of data about bacterial genes and gene expression, interpreting these data relies on many basic aspects of bacterial genetics, physiology, and ecology that are not yet well understood. N Impact of New Technologies ew approaches like genomics, transcriptomics, and proteomics allow the identification of the entire genetic complement of bacteria and which of these genes are turned on under particular conditions. Comparative genomics led to the discovery that gene exchange between bacteria is rampant and has dramatically influenced the acquisition of virulence, and had a major impact on our understanding of the evolution of pathogenesis. However, interpretation of data from these “omics” approaches relies on comparisons with databases rather than direct functional assays. Thus, these new approaches have not diminished the need for basic research because a detailed understanding of microbial physiology and genetics is essential to interpret and test the resulting predictions. In fact, the ability of “omics” approaches to generate a tremendous number of predictions greatly increases the need for direct experimental tests based upon genetics, biochemistry, and molecular biology. Furthermore, the detailed characterization of the mechanisms of discrete pathways and reactions, and molecular interactions that modulate these interactions is required for understanding the integrated networks and for developing new ways to modulate these processes for our purposes— a major goal of systems biology. Imaging is another technological advance that has provided useful insights into bacterial physiology and pathogenesis. Sensitive new approaches allow the visualization of molecules within bacteria and bacteria within an infected host. The applications of these approaches in bacterial cell biology and ecology have only begun to be tapped. Coupled with an understanding of bacterial physiology and molecular biology, and the ability to genetically manipulate these processes, will lead to new therapies that direct active agents to particular sites in the host to combat disease or stimulate health. Because of sophisticated instrumentation requirements and expense, efforts to develop these new technological approaches are typically restricted to large groups of scientists focused upon very specific problems. However, interpreting the vast amount of data generated by these new technologies and asking critical questions about what it means typically relies on individual scientists with unique expertise on a particular aspect of bacterial genetics, physiology, ecology, or molecular biology. To take optimal advantage of the intellectual capital spread across academia and industry, individual scientists should have access to the facilities needed to perform such experiments and the data generated from these experiments. Basic Research on Bacteria The Essential Frontier 3 Challenges and Opportunities There are many remaining challenges and corresponding opportunities. • Gene function—We need improved approaches for the rapid biochemical and genetic confirmation of predicted functions, as well as improved computational methods to accurately predict gene functions. A large number of genes have unknown functions. What are the “unknown” gene products doing? • Annotation—Misannotation of genes, including the prob- lem of derivative annotations, is a pervasive problem that can result in misleading interpretations of genomic data. • Metagenomics—Can we identify the roles of individual microbes present in complex microbial communities such as in the gut, in the oral cavity, on skin, etc.? To do so, we will need better algorithms to analyze short-single reads, assemble partial sequences, and recognize mechanisms that distinguish which functions rely on consortia of microbes vs. those that rely on individual microbes. This approach will allow us to identify which microbes comprise our normal biota and which others cause diseases as well as what diseases result from interactions between multiple microbes. • Metabolomics—We need new ways to quantify metabolic pools and flux through metabolic pathways to understand how genetic information is realized through various functions, especially in differing host environments. Applications of this technology include microbial forensics and enhanced production of useful metabolites by industry. • Systems biology—Because they are relatively simple and well-characterized, bacteria provide an excellent model system for systems biology. Multi-pronged studies on bacteria should allow us to couple the dynamics of metabolic pathways and regulatory networks to growth, adaptation, behavior, and population and community dynamics. In microbiology, the microbial community is ultimately the functioning unit of the system. Studying such interactions will require close collaborations between microbiologists, computer scientists, mathematicians, physicists, and engineers. 4 • Evolution—Bacterial evolution is now an experimental science that addresses the questions how and why. Cumulative results to date have changed our understanding of the evolution and spread of antibiotic resistance and emerging infectious diseases, but many fundamental questions remain. How do new strains evolve? Where do genetic islands come from? How does the acquisition and loss of genes influence fitness in the host and the environment? Can we identify mechanisms that will lead to the rapid identification of emerging infectious diseases? Can we impede this process? • Normal microbiota—Over the last few years, we have developed a better understanding of the impact of our natural microbiota on human health and disease, but these studies have also raised many new questions. How does natural microbial biota affect human development, nutrition, and disease resistance? What is the role of endogenous microbial biota in transfer of antibiotic resistance and virulence genes to potential pathogens? What determines whether metabolites produced by natural microbiota are used as beneficial nutrients or cause tissue damage in the host? How does the natural microbiota influence obesity, diabetes, and other chronic diseases? • In vitro culture studies—Laboratory studies are invaluable for studying bacterial physiology and genetics, facilitating the identification of new imetabolites, the manipulation of biochemical pathways for production of desired products, etc. However, the vast majority of bacteria are still uncultured. How can we culture previously uncultured organisms to allow studies in lab? • Transmission—We have learned many details of viru- lence factors in a variety of bacteria, but we do not yet understand many aspects of microbial ecology and environmental adaptation that allow bacteria to survive in the environment long enough to be transmitted to a new host. Understanding this process will demand expertise in microbial genetics, physiology, ecology, and mathematics. • Antimicrobials—We desperately need innovative approaches for the development of new classes of antibiotics (vs. simply modifying existing classes of antibiotics). Can we develop new methods to slow the development of antibiotic resistance? Are the current regimes of antibiotic therapy optimal? What does ecology tell us about predicting and managing antibiotic effectiveness? Answering these questions will demand collaborations between microbiologists, chemists, and physicians. • Immunity and tolerance—The human immune system is constantly interacting with the thousands of bacterial species comprising our natural microbiota. Understanding how the natural microbiota communicates with the immune system and how the immune system singles out harmful microorganisms could lead to the development of drugs that help the natural microbiota outcompete pathogens. • Vaccines—We need new types of vaccines that provide effective protective immunity and can be used in young children and individuals with compromised immune systems. Needs include more effective mechanisms of vaccine delivery, vaccine targets that provide broad, longlasting immunity, and vaccine formulations that are stable outside a narrow window of temperature and humidity conditions. Development of these vaccines will require integration of the fields of immunology, bacterial genetics, comparative genomics, bioinformatics, and pathogenesis. • Detection and identification—Rapid diagnostic tools to allow identification of the disease-causing agent and its resistance profile would make it possible to reduce the use of broad-spectrum antibiotics and encourage the development of targeted therapeutics that are less likely to disrupt the natural microbiota. • Chronic diseases—How do microbial infections stimulate chronic diseases? Once we understand how, can we develop new therapies to intervene and thus prevent this process? These questions extend to dental microbiology as well—for example, is there a relationship between periodontal disease and heart disease or premature births? • Host-bacteria interactions—Genes that influence estab- lishment of microbial populations may influence the ability of bacteria to cause disease. Identifying the host and bacterial genes that influence colonization and virulence, and studying the mechanics of the host-bacteria conversation, may provide a novel approach for countering infections. • Nanotechnology—To date most of our understanding of structure and function of bacteria comes from studies on populations of cells. However, averaging data from a large number of cells obscures important processes that occur with single cells. Similar arguments can be made for single molecules. Understanding structure and function at the single cell and single molecule level has important implications for nanotechnology. These questions are enticing a new generation of physicists into microbiology, but they are often hindered by inadequate understanding of bacterial physiology and genetics. • Bacterial physiology and genetics—Solving the problems described above demands a detailed understanding of basic molecular processes that mediate growth, metabolism, and regulation in microbial cells. Although commonly described in textbooks as if they are completely understood, there are many important, unresolved questions about basic bacterial genetics and physiology. For example, although when bacteria enter a host they must adapt to the increased temperature and osmolarity, we do not know how genes are regulated in response to these physical changes. In addition to insights on diseases, basic research on bacteria also leads to discoveries that benefit human health in other ways, including the development of new tools for cloning and gene expression, the modulation of metabolic pathways to overproduce useful end-products, the use of microbes for nanotechnology, the use of microbes for bioremediation of toxic waste and radioactivity, and the use of microbes for alternative energy production. Individual investigators with smaller lab groups provide the expertise needed to deal with the tremendous diversity of microbes, approaches, and scientific backgrounds required to solve these varied problems. However, human resources will need to be leveraged with shared access to sophisticated equipment to carry out research at the increasingly complex levels now possible. In addition, major efforts will be needed to capture, analyze, and share the prodigious streams of data already resulting from modern technological approaches. Individual laboratories will need access to the most efficient algorithms for such analyses, and access to tools that will allow them to create their own knowledge environments. Basic Research on Bacteria The Essential Frontier 5 M Is Larger Better? ost of the important discoveries in bacteriology have come from seemingly distant corners of basic research driven by individual investigators with small research groups. Some examples of such important discoveries include the growth of microbes in biofilms, the role of efflux systems in antibiotic resistance, the impact of gene amplification on the development of antibiotic resistance, the role of metabolic pathways (e.g. the glyoxylate shunt) on persistent infections, the role of normal flora in animal health, and the role of phage in the spread of bacterial toxins. These discoveries did not come from research efforts focused on a major initiative, but from research driven by basic scientific curiosity—a central premise of arguments by Vannavar Bush for the development of a federal research enterprise. Like travel on back roads vs. expressways, both routes have important but different roles—the expressway allows you to reach your destination faster but the back roads are likely to reveal exciting vistas that are hidden from the expressway. Likewise, research by smaller research groups provides creative fodder for larger focused research efforts aimed at countering infectious diseases, developing new antimicrobials, and detecting and thwarting potential bioterrorism agents. 6 T Educational Needs he fundamental concepts of bacterial physiology and genetics are essential for both basic and translational research. For example, an in-depth knowledge of bacterial physiology and genetics is essential for effective development of new antibiotics, thwarting antibiotic resistance, construction of novel vaccines, and treatment of diseases induced by asymptomatic infections. Bacteria are also vital to fields like chemical biology, biophysics, geobiology, and chemical engineering. However, newcomers from these other fields often lack core knowledge of basic bacterial physiology and genetics needed to integrate the disciplines. Training in basic research on bacteria also provides the skills needed in biotechnology, the pharmaceutical industry, and clinical microbiology. Individualized research allows a student to learn from mistakes and develop expertise in trouble-shooting scientific problems in close collaboration with a scientific mentor. However, there is concern in the research community that basic research in the microbial sciences has not flourished, resulting in fewer scientists actively working in this area and fewer students trained to respond to future microbial challenges. There is a widespread perception among microbiologists that enough scientists in bacterial physiology and genetics are not being trained, seriously jeopardizing science, medicine, and industry. There are several potential reasons for this neglect. First, other than the widespread publicity about the impact of antibiotic resistance, the community has done a poor job of explaining the importance of bacteria to the public. Because of this lack of awareness, there is no forceful public lobby promoting research on bacteria. In addition, this limits the exposure of young students to the exciting opportunities in this field. Second, over the last several decades there have been shifts in emphasis within academic institutions that have led to a decline in department support, hiring, and curriculum emphasis on microbiology; in some cases microbiological research has been subsumed within other departments, e.g., cell biology. Thus, despite the critical importance of microbiology research and education, many microbiology departments have shrunk or disappeared. B Summary asic research on bacteria has had significant impact on many areas of science. This research has revealed many fundamental features of all living cells, and has produced novel tools that allow us to study previously inaccessible problems. Discoveries continue to be made using model systems such as Escherichia coli and many other microbes with unique properties. Making discoveries often relies upon insights from studying the physiology and genetics of model organisms coupled with newly developed experimental tools and creative ideas. Thus, multiple perspectives provide the same answers to the two questions posed in the overview—there is a need for continued investment in basic research on bacteria, and a continuing major role for research by individual research groups. This raises the question: How can these objectives be met in a time of limited resources? One approach would be for the research community to tell its story in a manner that will make the points in this document clear to the public. Part of this story is a recognition of the significance of bacteria in basic biology, genetics, chronic disease, and nutrition as well as infectious disease. In addition, research on topics like evolution and ecology has a direct impact on the advancement of human health. Increased interagency cooperation could promote progress in these critical areas. “...research on topics like evolution and ecology has a direct impact on the advancement of human health.” Basic research on bacteria is a critical long-term investment for private and Federal research funding; it is vital to the development of applications that improve human health and well-being, and impacts our nationʼs economy. Applications of basic research on bacteria are essential for medicine, the pharmaceutical industry, biotechnology, bioremediation, and alternative energy production. Developing these applications will demand integration of many scientific disciplines. Given the importance of this field for the Federal mission and the interdisciplinary approaches required to exploit future challenges and opportunities, there is a continued need for basic research on bacteria. Basic Research on Bacteria The Essential Frontier 7 Selected Readings Altman et al. An open letter to Elias Zerhouni. Science, 307:1409 (2005). Backhed F., Ley R., Sonnenburg J., Peterson D., Gordon J. “Host-bacterial mutualism in the human intestine.” Science, 307: 1915-1920 (2005). Bush V. Science: The Endless Frontier. United States Government Printing Office, Washington, DC (1945) [available at http://www.nsf.gov/about/history/vbush1945.htm]. Fauci A. S., Zerhouni E. A. “NIH response to open letter.” Science, 308:49 (2005). Kaiser J. “Microbiology: Détente declared on NIH biodefense funding.” Science, 308:938 (2005). Maloy S., Schaechter M. “The era of microbiology: a Golden Phoenix.” International Microbiology, 9: 1-7 (2006). National Research Council. Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics. National Academies Press, Washington, DC (2006). Overbye K., Barrett J. “Antibiotics: where did we go wrong?” Drug Discovery Today, 10: 45-52 (2005). Schaechter M., Kolter R., Buckley M. Microbiology in the 21st Century: Where Are We and Where Are We Going? American Academy of Microbiology, Washington, DC (2003). Schlegel H. “Continuing opportunities for general microbiology.” Archives of Microbiology, 182: 105-108 (2004). Sleator R., Hill C. “Patho-biotechnology: using bad bugs to do good things.” Current Opinion in Biotechnology, 17: 211-216 (2006). “Applications of basic research on bacteria are essential for medicine, the pharmaceutical industry, biotechnology, bioremediation, and alternative energy production.” 8 Ecology and Evolution Appendix I Some examples that demonstrate the impact of basic research on bacteria are listed below. Molecular Biology • Cloning (plasmid and phage vectors; restriction enzymes) • DNA sequencing • PCR (Temperature stable polymerases) • Protein overexpression (phage T7; chaperones) • Protein secretion • Mutagenesis and DNA repair (discovered in bacteria; including mismatch repair which plays major role in certain cancers) • Recombination (including site-specific recombination systems used for genetic engineering, and mechanisms of homologous recombination) • Transposons (initial work in maize, but molecular understanding from work in bacteria) Metabolism and Biochemistry • Role of proton motive force in transport, energy (substrate coupled proton fluxes in bacteria) • LacY as paradigm for secondary transporters (many now implicated in disease) • Regulation of gene expression (via a diversity of mechanisms, including gene rearrangements, transcription, translation, turnover, etc.—most discovered by research in phage lambda and E. coli) • Extent of microbial diversity (>99% microbes uncultured; use of rRNA for taxonomy) • Evolution of new traits (acquisition of pathogenesis islands via horizontal gene transfer) • Coordination of microbial populations (quorum sensing) • Growth of mixed microbial consortia as biofilms Medicine • Discovery of antibiotics (streptomycin, tetracyclines, vancomycin, bactricin, etc.) • Antimetabolites (understanding of metabolic pathways led to improved therapies, e.g. trimethoprim plus sulfa) • Inhibitors of resistance mechanisms (e.g. ß-lactamase inhibitors such as clavulanic acid) • Discovery of gyrase and other topoisomerases (led to quinolone antibiotics such as ciprofloxacin, and anti-cancer drugs such as etoposides that make Type II topoisomerases toxic in rapidly dividing human cells) • Lipopolysaccharide structure (basis of septic shock) • Function of eukaryotic genes (comparative genomics of CFTR and P-glycoprotein sequences allowed prediction of their function based upon similarity to bacterial ABC transporters) • Live, attenuated vaccines (e.g. Aro mutants of Salmonella enterica sv. Typhi, required understanding of physiology) In addition to the above discoveries that emphasize the impact of microbiology prior to the last decade, some recent examples of discoveries resulting from basic research on bacteria include the following. Development of New Antibiotics and Inhibitors • Use of genomics to identify antibiotic targets and vaccine candidates • RNA and DNA aptamers as therapeutics (resulting from work on phage T4, aptamer-based treatments are currently in clinical trials) • Quorum sensing via homoserine lactones (required for virulence of some bacteria, inhibitors are being developed) • Antibiotic resistance due to efflux pumps (new inhibitors in trials) • Integrase inhibitors (studies on transposition mechanisms in bacteria leading to the understanding of the mechanism of HIV integrase, and the appreciation that this enzyme is a good target for drug development; novel peptide antibiotics that inhibit recombination) • Antibiotic target interactions informing modification of existing antibiotics (ribosome structure allows development of new aminoglycosides; penicillin binding proteins and mechanism of action of penicillins; mechanism of resistance to vancomycin; gyrase inhibitors, tRNA synthase inhibitor Mupirocin) • Determined sites of action for pesticides (including Roundup and the sulfonylurea herbicides) • Role of biofilms in antibiotic resistance and persistence (targets for novel antibiotics; tissues, implants, etc.) • Role of stress responses in antibiotic persistence and development of crossresistance • Phage therapy • Streptokinase as inhibitors of thrombosis subsequent to myocardial infarction Basic Research on Bacteria The Essential Frontier 9 Virulence Mechanisms • Cytoskeleton rearrangements modulated by bacteria (e.g. Listeria, Salmonella, etc.) • Growth of animal pathogens in plants (e.g. Salmonella) • Role of metabolites in virulence (e.g., Mg++ as signal of macrophage infection, relied upon basic studies of divalent ion transport) • Previously uncharacterized roles of host functions in defense (e.g. research in progress implicates Pon1 in host defense in liver and spleen tissues) Role of Bacteria in Chronic Disease • Bacteria cause or contribute to particular chronic diseases (opposing roles of Helicobacter in stomach and esophageal cancer; anaerobic consortia in periodontal disease; periodontal bacteria in atherosclerosis; etc.) • Role of periodontal bacteria in preterm births (previously overlooked because bacteria could not be cultivated) • Role of glyoxylate shunt in persistent infections by pathogens, including bacteria and fungi (relied upon basic understanding of pathway from work in E. coli) • Role of osmotic stress mechanisms (e.g. glycyl betaine and proline accumulation) in infectious disease (e.g. E. coli UTI, Staphylococcus) New Vaccines • Use of minicells as vaccine delivery systems • Edible vaccines (cheaper, do not need refrigeration, relied upon Agobacterium genetic engineering; e.g., hepatitis B vaccine in potatoes successful in initial human tests) • Use of live attenuated Salmonella strains to invoke mucosal immunity (relied upon understanding of basic physiology) • Use of Salmonella to deliver anti-cancer treatments (relied upon understanding of attachment/secretion systems) • Role of normal flora in development of host vascularization and immunity (e.g. Bacteriodes) Biotechnology (over 40% of biotech products made in the United States and European Union use E. coli as a host) • Identification of novel enzymes from extremophiles and “metagenome libraries” • Nutrients in genetically engineered crops (e.g. ß-catotene/Vitamin A in golden rice; plant genetic engineering relied upon basic research on Agobacterium) • Overproduction of membrane proteins in intracellular membranes of Rhodobacter (e.g. cystic fibrosis receptor) • Production of leucine-rich proteins for chemotherapy (initially failed because high level production leads to proteins with norleucine substituted for methionine, understanding of pathways gave the solution) • In vivo substitution of unusual amino acids (increased stability of therapeutic peptides; required basic understanding translation) • Tight on/off switches for gene expression 10 Detection of Pathogens • Rapid detection methods demand understanding of extent of gene exchange (e.g. phage-mediated mobility of exotoxin genes, transfer of antibiotic resistance, pathogenicity islands) • Array technologies to identify microbes and infections (required comparative genomics) • DNA-based rapid detection methods based upon comparative genomics • Protein-based detection of antibiotic resistance and toxins (based upon understanding physiology) • Metabolic-based detection (forensic microbiology relies on ability to trace minute metabolites) • Rapid breath tests for microbes (e.g., urease test for Helicobacter, others in development) • Identification of genetic determinants responsible for changes in host specificity associated with emerging infectious disease (relies on combination of genetics and comparative genomics) Bioinformatics • Correct annotation demands demonstration of functionality (direct genetic and physiological tests in model organisms, including bacteria and yeast; knowledge still inadequate) • Analysis of organisms that cannot be cultured (e.g., causative agent of syphilis) Laurie Comstock, Ph.D. Associate Professor of Medicine Channing Laboratory Brigham and Womenʼs Hospital Harvard Medical School Appendix II ASM-NIH Workshop on Bacterial Research participants. Steering Committee James Anderson, Ph.D. Program Director, Division of Genetics and Developmental Biology National Institutes of General Medical Sciences National Institutes of Health Dennis M. Dixon, Ph.D. Chief, Bacteriology and Mycology Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Carol A. Nacy, Ph.D. CEO, Sequella, Inc. James M. Tiedje, Ph.D. Professor, Center for Microbial Ecology Michigan State University General Meeting Participants Jonathan Beckwith, Ph.D. American Cancer Society Professor Department of Microbiology and Molecular Genetics Harvard Medical School Jorge Benach, Ph.D. Professor, Center for Infectious Diseases Stony Brook University Martin J. Blaser, M.D. Chair, NYU Department of Medicine New York University School of Medicine Richard H. Ebright, Ph.D. Professor and Investigator Howard Hughes Medical Institute at Rutgers University Claire M. Fraser-Liggett, Ph.D. President and Director, TIGR Nancy E. Freitag, Ph.D. Associate Professor, Seattle Biomedical Research Institute and Department of Pathobiology & Microbiology, University of Washington Stanley Maloy, Ph.D. Professor and Director Center for Microbial Sciences San Diego State University Frederick M. Ausubel, Ph.D. Professor of Genetics Department of Molecular Biology Massachusetts General Hospital Harvard Medical School J. Stephen Dumler, M.D. Professor of Pathology Division of Medical Microbiology, Department of Pathology The Johns Hopkins University School of Medicine George Georgiou, Ph.D. Cockrell Regents Endowed Chair in Engineering #9 Chemical Engineering, Biomedical Engineering and Institute for Cell and Molecular Biology University of Texas at Austin William R. Goldman, Ph.D. Professor of Molecular Microbiology Washington University School of Medicine Jeffrey Gordon, M.D. Professor and Director, Center for Genome Sciences Washington University Everett Peter Greenberg, Ph.D. Professor and Chair Department of Microbiology University of Washington Eduardo A. Groisman, Ph.D. Professor and Investigator Howard Hughes Medical Institute at the Washington University School of Medicine G. Wesley Hatfield, Ph.D. Professor, Department of Microbiology and Molecular Genetics University of California, Irvine School of Medicine Darren E. Higgins, Ph.D. Associate Professor, Department of Microbiology and Molecular Genetics Harvard Medical School Ann Hochschild, Ph.D. Professor, Department of Microbiology and Molecular Genetics Harvard Medical School William R. Jacobs, Jr., Ph.D. Professor and Investigator Howard Hughes Medical Institute at the Albert Einstein College of Medicine Samuel Kaplan, Ph.D. Professor and Chair, Microbiology and Molecular Genetics Department University of Texas Health Science Center Houston Medical School Paul Keim, Ph.D. Professor and Director Pathogen Genomics Translational Genomics Research Institute (TGEN) Northern Arizona University Linda J. Kenney, Ph.D. Associate Professor, Department of Microbiology & Immunology University of Illinois-Chicago Roberto Kolter, Ph.D. Professor, Microbiology and Molecular Genetics Harvard Medical School Robert Landick, Ph.D. Professor, Department of Bacteriology University of Wisconsin-Madison Robert A. LaRossa, Ph.D. Research Fellow, Central Research & Development DuPont Company Richard Lenski, Ph.D. Hannah Distinguished Professor Department of Microbiology & Molecular Genetics Michigan State University Mary E. Lidstrom, Ph.D. Associate Dean, Professor University of Washington Sheila A. Lukehart, Ph.D. Professor of Medicine University of Washington Basic Research on Bacteria The Essential Frontier 11 Joe Lutkenhaus, Ph.D. Professor, Department of Microbiology University of Kansas Medical Center Melvin Simon, Ph.D. Division of Biology California Institute of Technology Jeffery F. Miller, Ph.D. Professor and Chair, Department of Microbiology, Immunology and Molecular Genetics UCLA Magdalene So, Ph.D. Professor and Chair, Department of Molecular Microbiology & Immunology Oregon Health & Science University Charles P. Moran, Jr., Ph.D. Professor, Department of Microbiology & Immunology Emory University School of Medicine Shelley M. Payne, Ph.D. Professor, Department of Molecular Genetics and Microbiology University of Texas at Austin Malcolm E. Winkler, Ph.D. Professor, Department of Biology Indiana University Bloomington Kit Pogliano, Ph.D. Associate Professor Biological Sciences University of California, San Diego Ryland Young, Ph.D. Professor, Biochemistry/ Biophysics Department Texas A&M University Steve J. Projan, Ph.D. Vice President, Biological Technologies Wyeth Federal Meeting Participants Peg Riley, Ph.D. Professor, Biology Department University of Massachusetts Amherst Martin Rosenberg, Ph.D. Chief Scientific Officer Promega Corporation Lucia B. Rothman-Denes, Ph.D. Professor, Department of Molecular Genetics and Cell Biology The University of Chicago Molly Schmid, Ph.D. Keck Graduate Institute Olaf Schneewind, Ph.D., M.D. Professor, Department of Microbiology University of Chicago David H. Sherman, B.S., M.S., Ph.D. Professor, Life Sciences Institute University of Michigan Thomas J. Silhavy, Ph.D. Warner Lambert-Parke Davis Professor Molecular Biology Department Lewis Thomas Labs Princeton University 12 Gisela Storz, Ph.D. Senior Investigator Cell Biology and Metabolism Branch National Institute of Child Health and Human Development National Institutes of Health Patrick P. Dennis, Ph.D. Program Director Molecular and Cellular Biosciences National Science Foundation Daniel Drell, Ph.D. Program Manager, Life Sciences and Medical Sciences Division Office of Biological and Environmental Research U.S. Department of Energy Judith H. Greenberg, Ph.D. Director, Genetics and Developmental Biology National Institutes of General Medical Sciences/National Institutes of Health Maria Giovanni, Ph.D. Assistant Director for Microbial Genomics and Advanced Technologies National Institute of Allergy and Infectious Diseases National Institutes of Health Maryanna P. Henkart, Ph.D. Division Director Molecular and Cellular Biosciences National Science Foundation Dennis Mangan, Ph.D. Chief, Infectious Diseases and Immunity Branch National Institute of Child Health and Human Development National Institues of Health Barbara Mulach, Ph.D. Communications and Policy Team Leader National Institute of Allergy and Infectious Diseases National Institutes of Health Ann Lichens-Park, Ph.D. National Program Leader Competitive Programs U.S. Department of Agriculture Sam Perdue, Ph.D. Program Officer Bacteriology and Mycology Branch National Institute of Allergy and Infectious Diseases National Institutes of Health N. Kent Peters, Ph.D. Program Officer Bacteriology and Mycology Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Alexander Politis, Ph.D. Chief, Infectious Diseases and Microbiology IRG Center for Scientific Review National Institutes of Health Norka Ruiz-Bravo, Ph.D. Deputy Director for Extramural Research National Institutes of Health Michael Schaefer, Ph.D. Program Officer Bacteriology and Mycology Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Diane Stassi, Ph.D. Scientific Review Administrator Center for Scientific Review National Institutes of Health Starting with bottom row, left to right: Row 1: Linda J. Kenney, William R. Jacobs, Jr., Michael Schaefer, Magdalene So, Barbara Mulach Row 2: Frederick M. Ausubel, Stanley Maloy, Dennis Dixon, Melvin Simon, Laurie Comstock, William R. Goldman, Nancy E. Freitag Row 3: Roberto Kolter, Lucia B. RothmanDenes, Ann Hochschild, Patrick P. Dennis, J. Stephen Dumler Row 4: George Georgiou, Ryland Young, Richard Lenski, Shelley M. Payne, Everett Peter Greenberg Row 5: James M. Tiedje, James Anderson, Gisela Storz, Robert A. LaRossa Row 6: Thomas J. Silhavy, Sheila A. Lukehart, Dennis Mangan, Mary E. Lidstrom Row 7: Charles P. Moran, Diane Stassi, Malcolm E. Winkler, David H. Sherman, Robert Landick, Ann Lichens-Park, Daniel Drell, Peg Riley Row 8: Jeffrey Gordon, Molly Schmid, Kit Pogliano, Alexander Politis, Carol A. Nacy, Richard H. Ebright Row 9: N. Kent Peters, Claire M. FraserLiggett, Martin J. Blaser, Joe Lutkenhaus Row 10: Eduardo A. Groisman, Olaf Schneewind, Jeffery F. Miller, Darren E. Higgins, Jonathan Beckwith American Society for Microbiology 1752 N Street, NW Washington, DC 20036 Tel: 202-737-3600 www.asm.org