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Home , Bacteria, Bacteriology, Medical microbiology, Microbiological Research, Roberto Kolter

Basic Research on The Essential Frontier

Report on the American Society for and National Institutes of 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 . For more information about NIH and its programs, visit www.nih.gov The American Society for Microbiology (ASM) The ASM is the largest single science society, composed of over 42,000 and health profes - sionals. The ASM's mission is to promote research and research training in the microbiological sciences and to assist between scientists, policy makers and the public to improve health, economic -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 aureus — (MRSA bacterium) —rod prokaryote (bacterium) E. coli coli ( )—dividing, hemorrhagic 0157:H7 . © Dennis Kunkel www.denniskunkel.com Introduction

or many years the American Society for Microbiology (ASM) has been concerned about the need for increasing basic research in . This concern is based upon several premises, including: F 1 the widespread perception that an adequate number of researchers in the U.S. in fields such as bacterial and are not being trained, 2 the importance of basic knowledge of bacterial physiology and genetics in the industry and in applications including 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.

Approach Goal: The workshop participants focused on the he ASM-NIH workshop focused on scientific gaps and opportunities for research on bacteria. In order to stim - following discussion areas: Tulate creative, goal-oriented interactions, the meeting inte - grated focused discussions within smaller working groups • What are the gaps in our knowledge, methodologies, and overarching sessions with entire group participation. and information access that must be addressed? Participants in the two-day workshop included scientists What strategies would address these gaps? with a variety of research expertise, representatives of industry, and representatives of federal agencies. Following • How has at the basic and the meeting, the groupʼs Steering Committee prepared this applied levels been changed by technological advances summary of the discussions and recommendations to (e.g., , imaging, and computation)? What new guide future research. opportunities have been revealed?

• How have these technological advances altered the per - ception of what problems are interesting and important? What are the benefits and drawbacks to these changes?

• What factors have changed the marketplace for over the years and how? Is this picture changing again? What are the roles of the research insti - tutions 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 Overview Despite the broad impact of this , basic research on bacteria is at a crossroads. The research community acteria and their phages are the oldest and most perceives that public funding for most areas of basic abundant life forms on the planet. Bacteria have research, including bacteriology, has leveled off and that Bco-evolved with us and are beneficial for human health. There increased resources are being focused on infectious are over 10 more bacteria in our bodies than there research prompted in part by biodefense concerns. Coupled are human cells, and this natural is essential to this, large multi-investigator projects have emerged as an for proper development, nutrition, and resistance to disease. alternative to single investigator R01-type research projects. However, we also live in an environment replete with bacteria These developments raise the questions: What is the relative that can a wide variety of human diseases with value of continued investment in basic research on bacteria, bacterial responsible for 25 percent of human and is there a disproportionate emphasis on large scientific globally, a number predicted to increase dramatically consortia at the expense of research by smaller groups? with the growing crisis of resistance. We under - stand very little about the interactions between bacteria Evolving Priorities and the environment that influence the delicate ecological equilibrium between humans and microbes and thereby esearch on bacteria and their phages has led to many determine the balance between health and disease. fundamental scientific discoveries. Initial support for this Rresearch was justified in part because of the role of bacteria In addition to the bacteria that are in or on the , in causing disease. With the advent of effective it bacteria influence humans in many other ways. Bacteria are seemed like the war on microbes had been won. Hence, for the dominant occupant and architect of our entire . several decades health-related research shifted to topics Bacteria sustain the metabolic cycles that are essential for all like cancer, heart disease, and genetic diseases. Moreover, life on . Bacterial sculpts our physical envi - developments in molecular arising from research on ronment as well. Because they are ubiquitous and have such bacteria made it possible to study many basic biological diverse metabolic capabilities, bacteria influence essentially processes in mammalian cells, eliminating the argument all disciplines of science, including fields such as evolutionary that bacterial model systems were the only doorway to biology, , , and developmental biolo - eukaryotic . gy, psychology, , chemistry, physics, climatology, computer science, and engineering. Meanwhile, the microbes demonstrated how rapidly they could evolve new traits. Microbial resistance to antibiotics Bacteria are also instrumental for understanding funda - developed faster than new antibiotics could be developed, mental life processes that are required by all , and the resistance spread throughout the microbial world. including central metabolism, replication, , The global expansion of distribution networks facilitated , targeting, assembly and structure the rapid distribution of microbial . Simultaneously, of macromolecular complexes, , stress emerging microbial pathogens filled new ecological niches, responses, error correction mechanisms, signal , such as indwelling medical devices and the growing popula - and developmental programs. These processes are more tion of humans who are immunocompromised due to pri - easily characterized in model bacteria and their phages mary infections (including HIV) or due to used to than in other organisms because microbes provide such treat chronic diseases. Furthermore, recent discoveries tractable experimental systems. The large repertoire of have demonstrated that some diseases (including ulcers, genetic and biochemical tools and data that have been certain types of cancer, heart disease, etc.) that were pre - acquired from basic research on bacteria is crucial for viously believed to be caused by a genetic predisposition dissecting the complex metabolic and regulatory networks or exposure to environmental are actually caused by that control these processes. This provides a launching microbes. This microbial offensive has summoned a point for understanding the enormous diversity in the bacterial world and facilitates the understanding of these processes in .

2 renewed counter-attack on microbial pathogens. Impact of New Technologies Meanwhile, new tools have become available that make it possible to dissect the molecular basis of pathogenesis ew approaches like genomics, transcriptomics, and both from the microbial and perspectives. Recently, proteomics allow the identification of the entire genetic having the complete DNA sequences of bacterial Ncomplement of bacteria and which of these are turned pathogens has provided valuable insights into how micro - on under particular conditions. Comparative genomics led to bial pathogens evolve and the extent of transfer the discovery that gene exchange between bacteria is ram - between pathogens. These advances have revealed new pant and has dramatically influenced the acquisition of viru - ways to control , including the identification of lence, and had a major impact on our understanding of the novel targets for and novel approaches for of pathogenesis. However, interpretation of data development. from these “” approaches relies on comparisons with databases rather than direct functional assays. Thus, these The value of basic research on bacteria has extended well new approaches have not diminished the need for basic beyond infectious diseases. Research on bacteria led to research because a detailed understanding of microbial the elucidation of important concepts of molecular biology, physiology and genetics is essential to interpret and test the allowing developments in biotechnology that have yielded resulting predictions. In fact, the ability of “omics” approaches tremendous benefits to many other aspects of human to generate a tremendous number of predictions greatly health and well-being as well as providing new tools that increas es the need for direct experimental tests based have facilitated our understanding of pathogenesis. With upon genetics, , and molecular biology. the advent of new tools that allowed us to extend beyond Furthermore, the detailed characterization of the mecha - pure culture studies to identify bacteria in complex commu - nisms of discrete pathways and reactions, and molecular nities in the environment, it became clear that bacteria interactions that modulate these interactions is required for have many roles in human health that were previously understanding the integrated networks and for developing unknown. These discoveries have opened important new new ways to modulate these processes for our purposes— opportunities for research on bacteria. Although these new a major goal of systems biology. technologies allow the rapid accumulation of data about bacterial genes and , interpreting these Imaging is another technological advance that has provid - data relies on many basic aspects of bacterial genetics, ed useful insights into bacterial physiology and pathogene - physiology, and ecology that are not yet well understood. sis. Sensitive new approaches allow the visualization of molecules within bacteria and bacteria within an infected host. The applications of these approaches in bacterial 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, physiol - ogy, 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 and the data generated from these experiments.

Basic Research on Bacteria The Essential Frontier 3 Evolution Challenges and Opportunities • —Bacterial evolution is now an experimental science that addresses the questions how and why. There are many remaining challenges and Cumulative results to date have changed our understand - corresponding opportunities. ing of the evolution and spread of antibiotic resistance Gene function and emerging infectious diseases, but many fundamental • —We need improved approaches for the questions remain. How do new strains evolve? Where do rapid biochemical and genetic confirmation of predicted genetic islands come from? How does the acquisition and functions, as well as improved computational methods loss of genes influence fitness in the host and the envi - to accurately predict gene functions. A large number of ronment? Can we identify mechanisms that will lead to genes have unknown functions. What are the “unknown” the rapid identification of emerging infectious diseases? gene products doing? Can we impede this process? Annotation Normal microbiota • —Misannotation of genes, including the prob - • —Over the last few years, we have lem of derivative annotations, is a pervasive problem that developed a better understanding of the impact of our can result in misleading interpretations of genomic data. natural microbiota on human health and disease, but these studies have also raised many new questions. How • —Can we identify the roles of individual does natural microbial biota affect human development, microbes present in complex microbial communities such as nutrition, and disease resistance? What is the role of in the gut, in the oral cavity, on , etc.? To do so, we will endogenous microbial biota in transfer of antibiotic resist - need better algorithms to analyze short-single reads, ance and genes to potential pathogens? What assemble partial sequences, and recognize mechanisms determines whether metabolites produced by natural that distinguish which functions rely on consortia of microbes microbiota are used as beneficial nutrients or cause tis sue vs. those that rely on individual microbes. This approach will damage in the host? How does the natural microbiota allow us to identify which microbes comprise our normal influence obesity, diabetes, and other chronic diseases? biota and which others cause diseases as well as what dis - In vitro culture studies eases result from interactions between multiple microbes. • —Laboratory studies are invaluable Metabolomics for studying bacterial physiology and genetics, facilitating • —We need new ways to quantify metabolic the identification of new imetabolites, the manipulation of pools and flux through metabolic pathways to understand biochemical pathways for production of desired products, how genetic information is realized through various func - etc. However, the vast majority of bacteria are still uncul - tions, especially in differing host environments. Applications tured. How can we culture previously uncultured - of this technology include microbial forensics and enhanced isms to allow studies in lab? production of useful metabolites by industry. Systems biology • —We have learned many details of viru - • —Because they are relatively simple and lence factors in a variety of bacteria, but we do not yet well-characterized, bacteria provide an excellent model understand many aspects of and system for systems biology. Multi-pronged studies on environmental adaptation that allow bacteria to survive in bacteria should allow us to couple the dynamics of metabolic the environment long enough to be transmitted to a new pathways and regulatory networks to growth, adaptation, host. Understanding this process will demand expertise in behavior, and population and community dynamics. In , physiology, ecology, and mathematics. microbiology, the microbial community is ultimately the func - tioning unit of the system. Studying such interactions will require close collaborations between microbiologists, com - puter scientists, mathematicians, physicists, and engineers.

4 Antimicrobials Nanotechnology • —We desperately need innovative • —To date most of our understanding of approaches for the development of new classes of antibi - structure and function of bacteria comes from studies on otics (vs. simply modifying existing classes of antibiotics). populations of cells. However, averaging data from a Can we develop new methods to slow the development of large number of cells obscures important processes that antibiotic resistance? Are the current regimes of antibiotic occur with single cells. Similar arguments can be made optimal? What does ecology tell us about predict - for single molecules. Understanding structure and func - ing and managing antibiotic effectiveness? Answering tion at the single cell and single molecule level has these questions will demand collaborations between important implications for nanotechnology. These ques - microbiologists, chemists, and . tions are enticing a new generation of physicists into Immunity and tolerance microbiology, but they are often hindered by inadequate • —The human understanding of bacterial physiology and genetics. is constantly interacting with the thousands of bacterial Bacterial physiology and genetics comprising our natural microbiota. Understanding • —Solving the problems how the natural microbiota communicates with the immune described above demands a detailed understanding of system and how the immune system singles out harmful basic molecular processes that mediate growth, metabo - could lead to the development of drugs lism, and regulation in microbial cells. Although commonly that help the natural microbiota outcompete pathogens. described in textbooks as if they are completely understood, there are many important, unresolved questions about • —We need new types of vaccines that provide basic bacterial genetics and physiology. For example, effective protective immunity and can be used in young although when bacteria enter a host they must adapt to the children and individuals with compromised immune sys - increased temperature and osmolarity, we do not know how tems. Needs include more effective mechanisms of vac - genes are regulated in response to these physical changes. cine delivery, vaccine targets that provide broad, long- lasting immunity, and vaccine formulations that are stable In addition to insights on diseases, basic research on outside a narrow window of temperature and humidity bacteria also leads to discoveries that benefit human conditions. Development of these vaccines will require health in other ways, including the development of new integration of the fields of immunology, bacterial genetics, tools for cloning and gene expression, the modulation of comparative genomics, bioinformatics, and pathogenesis. metabolic pathways to overproduce useful end-products, Detection and identification the use of microbes for nanotechnology, the use of microbes • —Rapid diagnostic tools to for of and radioactivity, and the allow identification of the disease-causing agent and its use of microbes for alternative production. resistance profile would make it possible to reduce the use of broad-spectrum antibiotics and encourage the Individual investigators with smaller lab groups provide the development of targeted therapeutics that are less likely expertise needed to deal with the tremendous diversity of to disrupt the natural microbiota. microbes, approaches, and scientific backgrounds required to Chronic diseases solve these varied problems. However, human resources will • —How do microbial infections stimulate need to be leveraged with shared access to sophisticated chronic diseases? Once we understand how, can we equipment to carry out research at the increasingly complex develop new therapies to intervene and thus prevent this levels now possible. In addition, major efforts will be needed process? These questions extend to dental microbiology to capture, analyze, and share the prodigious streams of data as well—for example, is there a relationship between peri - already resulting from modern technological approaches. odontal disease and heart disease or premature births? Individual laboratories will need access to the most efficient Host-bacteria interactions algorithms for such analyses, and access to tools that will • —Genes that influence estab - allow them to create their own knowledge environments. 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 study - ing the mechanics of the host-bacteria conversation, may provide a novel approach for countering infections.

Basic Research on Bacteria The Essential Frontier 5 Is Larger Better? Educational Needs

ost of the important discoveries in bacteriology have he fundamental concepts of bacterial physiology and come from seemingly distant corners of basic genetics are essential for both basic and translational Mresearch driven by individual investigators with small Tresearch. For example, an in-depth knowledge of bacterial research groups. Some examples of such important dis - physiology and genetics is essential for effective develop - coveries include the growth of microbes in , the ment of new antibiotics, thwarting antibiotic resistance, con - role of efflux systems in antibiotic resistance, the impact of struction of novel vaccines, and treatment of diseases gene amplification on the development of antibiotic resist - induced by asymptomatic infections. Bacteria are also vital ance, the role of metabolic pathways (e.g. the glyoxylate to fields like chemical biology, biophysics, , and shunt) on persistent infections, the role of normal in chemical engineering. However, newcomers from these health, and the role of phage in the spread of bac - other fields often lack core knowledge of basic bacterial terial toxins. These discoveries did not come from research physiology and genetics needed to integrate the disciplines. efforts focused on a major initiative, but from research driv - en by basic scientific curiosity—a central premise of argu - Training in basic research on bacteria also provides the ments by Vannavar Bush for the development of a federal skills needed in biotechnology, the , research enterprise. Like travel on back roads vs. express - and clinical microbiology. Individualized research allows a ways, both routes have important but different roles—the student to learn from mistakes and develop expertise in expressway allows you to reach your destination faster but trouble-shooting scientific problems in close collaboration the back roads are likely to reveal exciting vistas that are with a scientific mentor. However, there is concern in the hidden from the expressway. Likewise, research by smaller research community that basic research in the microbial research groups provides creative fodder for larger sciences has not flourished, resulting in fewer scientists focused research efforts aimed at countering infectious dis - actively working in this area and fewer students trained to eases, developing new antimicrobials, and detecting and respond to future microbial challenges. thwarting potential agents. There is a widespread perception among microbiologists that enough scientists in bacterial physiology and genetics are not being trained, seriously jeopardizing science, , 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.

6 Summary

asic research on bacteria has had significant impact on many areas of science. This research has revealed Bmany fundamental features of all living cells, and has produced novel tools that allow us to study previously inac - cessible problems. Discoveries continue to be made using model systems such as 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 devel - oped experimental tools and creative ideas. Thus, multiple perspectives provide the same answers to “...research on topics like the two questions posed in the overview—there is a need for continued investment in basic research on bacteria, and evolution and ecology a continuing major role for research by individual research groups. This raises the question: How can these objectives has a direct impact on be met in a of limited resources? One approach would be for the research community to tell its story in a manner the advancement of that will make the points in this document clear to the public. Part of this story is a recognition of the significance human health.” 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.

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 Science Altman et al. An open letter to Elias Zerhouni. , 307:1409 (2005).

Backhed F., Ley R., Sonnenburg J., Peterson D., Gordon J. “Host-bacterial in the human intestine.” Science , 307: 1915-1920 (2005). Science: The Endless Frontier Bush V. . United States Government Printing Office, Washington, DC (1945) [available at http://www.nsf.gov/about/history/vbush1945.htm ]. Science Fauci A. S., Zerhouni E. A. “NIH response to open letter.” , 308:49 (2005). Science Kaiser J. “Microbiology: Détente declared on NIH biodefense funding.” , 308:938 (2005). International Microbiology Maloy S., Schaechter M. “The era of microbiology: a Golden Phoenix.” , 9: 1-7 (2006). Treating Infectious Diseases in a Microbial World: Report of Two Workshops National Research Council. on Novel Therapeutics . National Academies Press, Washington, DC (2006). Drug Discovery Today Overbye K., Barrett J. “Antibiotics: where did we go wrong?” , 10: 45-52 (2005). Microbiology in the 21st Century: Where Are We and Where Are We Going Schaechter M., Kolter R., Buckley M. ? American Academy of Microbiology, Washington, DC (2003). Archives of Microbiology Schlegel H. “Continuing opportunities for general microbiology.” , 182: 105-108 (2004). Current Opinion in Biotechnology Sleator R., Hill C. “Patho-biotechnology: using bad bugs to do good things.” , 17: 211-216 (2006).

“Applications of basic research on bacteria are essential for medicine, the pharmaceutical industry, biotechnology, bioremediation, and alternative energy production.”

8 I Ecology and Evolution In addition to the above discoveries that emphasize the impact of microbiology prior • Extent of microbial diversity (>99% to the last decade, some recent examples Some examples that demonstrate the microbes uncultured; use of rRNA for of discoveries resulting from basic impact of basic research on bacteria are ) research on bacteria include the following. listed below. • Evolution of new traits (acquisition of Development of New Antibiotics Molecular Biology pathogenesis islands via ) and Inhibitors • Cloning ( and phage vectors; • Coordination of microbial populations • Use of genomics to identify antibiotic restriction ) () targets and vaccine candidates • DNA • Growth of mixed microbial consortia as • RNA and DNA as therapeutics • PCR (Temperature stable ) biofilms (resulting from work on phage T4, • Protein overexpression (phage T7; Medicine -based treatments are currently chaperones) in clinical trials)

• Protein • Discovery of antibiotics (streptomycin, • Quorum sensing via homoserine lactones (required for virulence of some bacteria, • Mutagenesis and DNA repair (discovered tetracyclines, , bactricin, etc.) inhibitors are being developed) in bacteria; including mismatch repair • Antimetabolites (understanding of metabol - which plays major role in certain cancers) ic pathways led to improved therapies, e.g. • Antibiotic resistance due to efflux pumps (new inhibitors in trials) • Recombination (including site-specific trimethoprim plus sulfa) recombination systems used for genetic • Inhibitors of resistance mechanisms • Integrase inhibitors (studies on transposi - engineering, and mechanisms of homolo - (e.g. ß-lactamase inhibitors such as tion mechanisms in bacteria leading to gous recombination) ) the understanding of the mechanism of HIV integrase, and the appreciation that • Transposons (initial work in , but • Discovery of gyrase and other topoiso - this is a good target for drug molecular understanding from work in merases (led to quinolone antibiotics development; novel antibiotics bacteria) such as ciprofloxacin, and anti-cancer that inhibit recombination) drugs such as etoposides that make Metabolism and Biochemistry Type II topoisomerases toxic in rapidly • Antibiotic target interactions informing dividing human cells) modification of existing antibiotics (ribo - • Role of proton motive force in transport, some structure allows development of • structure (basis of energy (substrate coupled proton fluxes new aminoglycosides; binding septic ) in bacteria) and mechanism of action of • Function of eukaryotic genes (comparative ; mechanism of resistance to • LacY as paradigm for secondary trans - genomics of CFTR and P-glycoprotein vancomycin; gyrase inhibitors, tRNA syn - porters (many now implicated in disease) sequences allowed prediction of their func - thase inhibitor Mupirocin) tion based upon similarity to bacterial ABC • Regulation of gene expression (via a • Determined sites of action for transporters) diversity of mechanisms, including gene (including Roundup and the sulfonylurea rearrangements, transcription, translation, • Live, attenuated vaccines (e.g. Aro herbicides) turnover, etc.—most discovered by enterica E. coli mutants of sv. Typhi, research in phage lambda and ) • Role of biofilms in antibiotic resistance and required understanding of physiology) persistence (targets for novel antibiotics; tissues, implants, etc.) • Role of stress responses in antibiotic persistence and development of cross- resistance • • as inhibitors of thrombosis subsequent to myocardial infarction

Basic Research on Bacteria The Essential Frontier 9 Virulence Mechanisms New Vaccines Detection of Pathogens

• rearrangements modulated • Use of minicells as vaccine delivery systems • Rapid detection methods demand , Salmonella, by bacteria (e.g. etc.) understanding of extent of gene • Edible vaccines (cheaper, do not need Agobacterium exchange (e.g. phage-mediated mobility • Growth of animal pathogens in refrigeration, relied upon Salmonella of genes, transfer of antibiotic (e.g. ) ; e.g., B resistance, pathogenicity islands) vaccine in potatoes successful in initial • Role of metabolites in virulence (e.g., human tests) • Array technologies to identify microbes Mg ++ as signal of infection, Salmonella and infections (required comparative relied upon basic studies of divalent • Use of live attenuated strains genomics) transport) to invoke mucosal immunity (relied upon understanding of basic physiology) • DNA-based rapid detection methods • Previously uncharacterized roles of host Salmonella based upon comparative genomics functions in defense (e.g. research in • Use of to deliver anti-cancer progress implicates Pon1 in host defense treatments (relied upon understanding of • Protein-based detection of antibiotic in liver and spleen tissues) attachment/secretion systems) resistance and toxins (based upon understanding physiology) Role of Bacteria in Chronic Disease • Role of normal flora in development of host vascularization and immunity (e.g. • Metabolic-based detection (forensic Bacteriodes) microbiology relies on ability to trace • Bacteria cause or contribute to particular minute metabolites) chronic diseases (opposing roles of Biotechnology (over 40% of • Rapid breath tests for microbes (e.g., in and esophageal biotech products made in the Helicobacter cancer; anaerobic consortia in periodontal test for , others in disease; periodontal bacteria in atheroscle - United States and European development) rosis; etc.) Union use E. coli as a host) • Identification of genetic determinants responsible for changes in host specifici - • Role of periodontal bacteria in preterm • Identification of novel enzymes from ty associated with emerging infectious births (previously overlooked because and “metagenome disease (relies on combination of genet - bacteria could not be cultivated) libraries” ics and comparative genomics) • Role of glyoxylate shunt in persistent • Nutrients in genetically engineered crops Bioinformatics infections by pathogens, including (e.g. ß-catotene/ A in golden rice; bacteria and fungi (relied upon basic genetic engineering relied upon • Correct annotation demands demonstra - understanding of pathway from work Agobacterium E. col i basic research on ) tion of functionality (direct genetic and in ) • Overproduction of membrane proteins in physiological tests in model organisms, • Role of osmotic stress mechanisms (e.g. intracellular membranes of including bacteria and ; knowledge glycyl betaine and accumulation) (e.g. receptor) still inadequate) E. coli in infectious disease (e.g. UTI, Staphylococcus • Production of leucine-rich proteins for • Analysis of organisms that cannot ) (initially failed because be cultured (e.g., causative agent high level production leads to proteins of ) with norleucine substituted for , understanding of pathways gave the solution) • In vivo substitution of unusual amino acids (increased stability of therapeutic ; required basic understanding translation) • Tight on/off switches for gene expression

10 Laurie Comstock, Ph.D. Darren E. Higgins, Ph.D. Appendix II Associate Professor of Medicine Associate Professor , Department of ASM-NIH Workshop on Bacterial Channing Laboratory Microbiology and Research participants. Brigham and Womenʼs Hospital Harvard Harvard Medical School Ann Hochschild, Ph.D. Steering Committee J. Stephen Dumler, M.D. Professor Professor of , Department of Microbiology James Anderson, Ph.D. and Molecular Genetics Program Director Division of , Harvard Medical School , Division of Genetics Department of Pathology and William R. Jacobs, Jr., Ph.D. The Johns Hopkins University Professor and Investigator National Institutes of General Medical Sciences School of Medicine National Institutes of Health Richard H. Ebright, Ph.D. Howard Hughes Medical Institute at the Dennis M. Dixon, Ph.D. Professor and Investigator Albert Einstein College of Medicine Chief , Bacteriology and Branch Samuel Kaplan, Ph.D. Howard Hughes Medical Institute at Professor and Chair Division of Microbiology and Infectious Diseases Rutgers University , Microbiology National Institute of and Molecular Genetics Department and Infectious Diseases Claire M. Fraser-Liggett, Ph.D. President and Director University of Texas Health Science Center National Institutes of Health , TIGR Houston Medical School Stanley Maloy, Ph.D. Nancy E. Freitag, Ph.D. Paul Keim, Ph.D. Professor and Director Associate Professor Professor and Director , Seattle Biomedical Center for Microbial Sciences Research Institute and Genomics San Diego State University Department of Pathobiology & Microbiology, Translational Genomics Carol A. Nacy, Ph.D. University of Washington Research Institute (TGEN) CEO Northern Arizona University , Sequella, Inc. George Georgiou, Ph.D. Cockrell Regents Endowed Linda J. Kenney, Ph.D. James M. Tiedje, Ph.D. Chair in Engineering #9 Associate Professor Professor , Department of , Center for Microbial Ecology Chemical Engineering , Biomedical Microbiology & Immunology Michigan State University Engineering and Institute for Cell and University of Illinois-Chicago Molecular Biology , Ph.D. General Meeting Participants University of Texas at Austin Professor William R. Goldman, Ph.D. , Microbiology and Frederick M. Ausubel, Ph.D. Professor of Molecular Microbiology Molecular Genetics Professor of Genetics Harvard Medical School Washington University School of Medicine Department of Molecular Biology Robert Landick, Ph.D. Massachusetts General Hospital Jeffrey Gordon, M.D. Professor, Professor and Director Department of Bacteriology Harvard Medical School , Center for University of Wisconsin-Madison Jonathan Beckwith, Ph.D. Sciences Robert A. LaRossa, Ph.D. American Cancer Society Professor Washington University Research Fellow , Central Research & Department of Microbiology and Everett Peter Greenberg, Ph.D. Professor and Chair Development Molecular Genetics DuPont Company Harvard Medical School Department of Microbiology Richard Lenski, Ph.D. Jorge Benach, Ph.D. University of Washington Hannah Distinguished Professor Professor , Center for Eduardo A. Groisman, Ph.D. Professor and Investigator Department of Microbiology & Infectious Diseases Molecular Genetics Stony Brook University Howard Hughes Medical Institute at the Michigan State University Martin J. Blaser, M.D. Washington University School of Medicine Mary E. Lidstrom, Ph.D. Chair , NYU Department of Medicine G. Wesley Hatfield, Ph.D. Associate Dean Professor , Professor New York University School , Department of Microbiology and University of Washington of Medicine Molecular Genetics Sheila A. Lukehart, Ph.D. University of California, Irvine Professor of Medicine School of Medicine University of Washington

Basic Research on Bacteria The Essential Frontier 11 Joe Lutkenhaus, Ph.D. Melvin Simon, Ph.D. Dennis Mangan, Ph.D. Professor Chief , Department of Microbiology Division of Biology , Infectious Diseases University of Kansas Medical Center California Institute of Technology and Immunity Branch Jeffery F. Miller, Ph.D. Magdalene So, Ph.D. National Institute of Child Health Professor and Chair Professor and Chair and Human Development , Department of , Department of National Institues of Health Microbiology, Immunology and Molecular Molecular Microbiology & Immunology Barbara Mulach, Ph.D. Genetics Oregon Health & Science University and UCLA Gisela Storz, Ph.D. Policy Team Leader Charles P. Moran, Jr., Ph.D. Senior Investigator Professor National Institute of Allergy , Department of Cell Biology and Metabolism Branch and Infectious Diseases Microbiology & Immunology National Institute of Child Health National Institutes of Health Emory University School of Medicine and Human Development Ann Lichens-Park, Ph.D. Shelley M. Payne, Ph.D. National Institutes of Health National Program Leader Professor Malcolm E. Winkler, Ph.D. Competitive Programs , Department of Molecular Genetics Professor and Microbiology , Department of Biology U.S. Department of University of Texas at Austin Indiana University Bloomington Sam Perdue, Ph.D. Kit Pogliano, Ph.D. Ryland Young, Ph.D. Program Officer Bacteriology Associate Professor Professor and Mycology Branch , Biochemistry/ Biological Sciences Biophysics Department National Institute of Allergy University of California, San Diego Texas A&M University and Infectious Diseases Steve J. Projan, Ph.D. National Institutes of Health Vice President N. Kent Peters, Ph.D. , Biological Technologies Federal Meeting Participants Program Officer Bacteriology Wyeth Patrick P. Dennis, Ph.D. and Mycology Branch Peg Riley, Ph.D. Program Director Molecular Professor and Cellular Biosciences National Institute of Allergy , Biology Department and Infectious Diseases University of Massachusetts Amherst National Science Foundation National Institutes of Health Martin Rosenberg, Ph.D. Daniel Drell, Ph.D. Alexander Politis, Ph.D. Chief Scientific Officer Program Manager, Chief Life Sciences , Infectious Diseases Promega Corporation and Medical Sciences Division and Microbiology IRG Lucia B. Rothman-Denes, Ph.D. Office of Biological and Center for Scientific Review Professor Environmental Research National Institutes of Health , Department of Molecular U.S. Department of Energy Genetics and Cell Biology Norka Ruiz-Bravo, Ph.D. Judith H. Greenberg, Ph.D. The University of Chicago Deputy Director for Extramural Research Director Molly Schmid, Ph.D. , Genetics and National Institutes of Health Developmental Biology Michael Schaefer, Ph.D. Keck Graduate Institute National Institutes of General Medical Program Officer Bacteriology Sciences/National Institutes of Health Olaf Schneewind, Ph.D., M.D. and Mycology Branch Professor Maria Giovanni, Ph.D. , Department of Microbiology Assistant Director for Microbial National Institute of Allergy University of Chicago Genomics and Advanced Technologies and Infectious Diseases David H. Sherman, B.S., M.S., Ph.D. National Institutes of Health National Institute of Allergy and Professor Diane Stassi, Ph.D. , Life Sciences Institute Infectious Diseases Scientific Review Administrator University of Michigan National Institutes of Health Thomas J. Silhavy, Ph.D. Maryanna P. Henkart, Ph.D. Center for Scientific Review Warner Lambert-Parke Davis Professor Division Director Molecular National Institutes of Health Molecular Biology Department and Cellular Biosciences Lewis Thomas Labs National Science Foundation Princeton University

12 Starting with bottom row, left to right: Linda J. Kenney, William R. Jacobs, Row 1: Jr., Michael Schaefer, Magdalene So, Barbara Mulach

Frederick M. Ausubel, Row 2: Stanley Maloy, Dennis Dixon, Melvin Simon, Laurie Comstock, William R. Goldman, Nancy E. Freitag

Roberto Kolter, Lucia B. Rothman- Row 3: Denes, Ann Hochschild, Patrick P. Dennis, J. Stephen Dumler

George Georgiou, Ryland Young, Row 4: Richard Lenski, Shelley M. Payne, Everett Peter Greenberg

James M. Tiedje, James Anderson, Row 5: Gisela Storz, Robert A. LaRossa

Thomas J. Silhavy, Sheila A. Lukehart, Row 6 : Dennis Mangan, Mary E. Lidstrom

Charles P. Moran, Diane Stassi, Row 7: Malcolm E. Winkler, David H. Sherman, Robert Landick, Ann Lichens-Park, Daniel Drell, Peg Riley

Jeffrey Gordon, Molly Schmid, Row 8: Kit Pogliano, Alexander Politis, Carol A. Nacy, Richard H. Ebright

N. Kent Peters, Claire M. Fraser- Row 9: Liggett, Martin J. Blaser, Joe Lutkenhaus

Eduardo A. Groisman, Row 10: 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