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Workshop Overview
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From page 1...
... . The Emerging Infections report helped to define the factors and dynamic relationships that lead to the emergence of infectious diseases.
From page 2...
... Through invited presentations and discussions, participants explored a range of topics related to microbial evolution and co-adaptation, including: methods for characterizing microbial diversity; model systems for investigating the ecology of host-microbe interactions and microbial communities at the molecular level; microbial evolution and the emergence of virulence; the phenomenon of antibiotic resistance and opportunities for mitigating its public health impact; and an exploration of current trends in infectious disease emergence as a means to anticipate the appearance of future novel pathogens.
From page 3...
... These proceedings summarize only the statements of participants in the workshop and are not intended to be an exhaustive exploration of the subject matter or a representation of consensus evaluation. THE LIFE AND LEGACIES OF JOSHUA LEDERBERG This workshop continued the tradition established by the late Joshua Lederberg, this Forum's first chairman, of wide-ranging discussion among experts from many disciplines and sectors, honoring him by focusing on fields of inquiry to which he had made important contributions.
From page 4...
... the area of infectious diseases, as epitomized by the Forum. Indeed, Forum member Stanley Lemon,3 of the University of Texas Medical Branch in Galveston, observed that the Forum's mission -- "tackling tough problems and addressing them with the best of science from the academic perspective and the active involvement of government" -- is now borne by scores of people who can only hope to carry out what Lederberg once undertook single-handedly.
From page 5...
... government with a basis for developing a national strategy on emerging infections and informed the pursuit of international negotiations to address this threat -- the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID)
From page 6...
... From his early, Nobel Prize–winning work on bacterial recombination, accomplished while he was barely 20, through the last years of his life, when he continued to provide much sought-after advice to global policy makers on emerging infectious diseases and biological warfare, Lederberg extended his command of microbiology to profoundly influence a host of related fields, including biotechnology, artificial intelligence, bioinformatics, and exobiology. Exobiology, the study of extraterrestrial life, was one among many widely used terms coined by Lederberg, according to Stephen Morse.
From page 7...
... This habit was still in evidence in the early 1990s during his cochairmanship of the first IOM study on emerging infections, according to Forum member Enriqueta (Queta) Bond, president of the Burroughs Wellcome Fund.
From page 8...
... The final changes in the book -- all improvements -- were due to that conversation." Academic Another tribute to Lederberg's remarkable capacities was institutional innovation, Hamburg observed. When Lederberg created departments of genetics in the medical schools at the University of Wisconsin and Stanford University, Hamburg recalled, "[the field of]
From page 9...
... "You might have thought, in 1996, that Fogarty and the 5 In the mid-1990s, Barry Bloom was a Howard Hughes Medical Institute investigator and served on the National Advisory Board of the Fogarty International Center at the National Institutes of Health; see http://www.hsph.harvard.edu/administrative-offices/deans-office/dean-barry-r-bloom/.
From page 10...
... and was particularly influential as that organization attempted to establish regional surveillance centers for emerging infectious diseases. Forum member James Hughes, of Emory University, remarked that Lederberg was "very engaged in Geneva, to the point that he took it upon himself to meet with the director-general of the WHO at the time, Dr.
From page 11...
... "He strongly influenced the negotiation of the biological weapons disarmament treaty."8 When Lederberg first voiced his concerns regarding emerging microbial threats in the late 1980s, Mahmoud recalled, "half of the scientific community was just smiling [as if to say] , ‘the old man is just babbling about the subject.'" Instead, the advent of "a fundamental platform," the 1992 IOM report, "really opened the way for a new way of thinking about microbes .
From page 12...
...  A Human African trypanosomiasis Cholera Marburg haemorrhagic fever MDR/XDR tuberculosis Plague Human monkeypox Chikungunya fever Enterovirus 71 Hendra virus Nipah virus Vancomycin-resistant Staphylococcus aureus H5N1 influenza Escherichia coli O157:H7 SARS Anthrax bioterrorism† Hantavirus pulmonary syndrome Typhoid fever Dengue Rift Valley fever Yellow fever Diphtheria HIV Drug-resistant malaria Lassa fever Ebola haemorrhagic fever Lyme disease Cryptosporidiosis Hepatitis C West Nile virus vCJD Cyclosporiasis B The French pox (syphilis) , 1494 The American plague (yellow fever)
From page 13...
... (A) Selected emerging diseases of public-health importance in the past 30 years (1977-2007)
From page 14...
... Forum co-chair Peggy Hamburg -- whose experiences with Lederberg evolved from those of a young daughter of a colleague (exploring tidal pools) to that of a professional peer (co-chairing the IOM Committee on Microbial Threats to Health in the 21st Century)
From page 15...
... . and through conversation with that person, to get some idea of what was going on in many different fields," David Hamburg recalled.
From page 16...
... "He had great confidence in the ability of scientists and researchers to continue to solve some of the riddles that still confront science in the fight against infectious diseases. By remembering him with this tribute, we are also remembering the many things that his life and career can teach all of us.
From page 17...
... and reemergent (e.g., influenza) infectious diseases; lethal outbreaks of Ebola, hantavirus, and other exotic viruses of animal origin; and a new appreciation for the infectious etiology of a variety of chronic diseases, including the association of peptic ulcer with Helicobacter pylori infection, liver cancer with hepatitis B and C viruses, and Lyme arthritis with Borrelia burgdorferi, to name a few.
From page 18...
... Equally complex "host-less" microbial communities exist in the form of biofilms -- complex aggregations of microorganisms that grow on solid substrates -- as described by speaker Jill Banfield of the University of California, Berkeley. The diversity of mutually beneficial host-microbe interactions was reflected in a pair of presentations by Margaret McFall-Ngai and Jean-Michel Ané, both of the University of Wisconsin, Madison, who described the symbiotic relationships between bacteria and eukaryotes that either allow squids to camouflage themselves from aquatic predators, or enable plants to acquire nutrients through their roots.
From page 19...
... Through their explorations of the human microbiome, Relman and coworkers seek to understand the role of indigenous microbial communities associated with human health, disease, and the various transition states in between. By understanding essential features of symbiotic relationships between microbial communities and their human hosts, they hope eventually to be able to predict host phenotypes -- such as health status -- that are associated with particular features of indigenous communities, and potentially manipulate these communities to restore or preserve health.
From page 20...
... 20 MICROBIAL EVOLUTION AND CO-ADAPTATION Relative Abundance (% Total Bacteria) FIGURE WO-2  Temporal  profiles  of  the COLOR.eps Figure WO-2 most  abundant  level  3  taxonomic  groups.  bitmap image Level 3 taxonomic groups were selected for display if their mean (normalized)
From page 21...
... It also invites an ecological view of infectious disease control that seeks to restore community equilibrium following disturbance. In order to study the effects of such disturbances, Relman and coworkers have examined patterns of microbial diversity in the human gut before, during, and after deliberate, periodic, exposure of healthy human subjects to the antibiotic ciprofloxacin.
From page 22...
... . Banfield and coworkers use mine-derived biofilms as a model system to examine how relatively simple microbial communities (that is, communities dominated by a few types of organisms)
From page 23...
... . Banfield's group has also examined the role of viruses in biofilms, and particularly the viral "predators" of the dominant bacterial species in these communities.
From page 24...
...  MICROBIAL EVOLUTION AND CO-ADAPTATION FIGURE WO-3 Six genotypes of Leptospirillum group II bacteria were detected in the Figure WO-3 COLOR.eps Richmond Mine (Iron Mountain, CA) by proteomic-inferred genome typing and inferred bitmap image to have arisen via homologous recombination between parental genotypes.
From page 25...
... contigs Figure WO-4 COLOR.eps were clustered based on tetranucleotide frequencies (left panel) , and CRISPRs were clus bitmap image tered based on patterns of SNC contig matching (right panel)
From page 26...
... , as well as the two systems described in workshop presentations and discussed below: plant roots and the light organ of the Hawaiian squid. Plant Root Symbionts In relationships somewhat analogous to those that exist between mammals and their gastrointestinal microbiota, plants establish mutualistic associations CHEATER + Parasitism Parasitism Commensalism Mutualism Species 0 Competition Neutralism Commensalism "A" – Competition Competition Parasitism – 0 + Species "B" FIGURE WO-5 The symbiotic continuum.
From page 27...
... The fungi release diffusible compounds known as ARBUSCULAR HOST LEGUME PLANT RHIZOBIA MYCORRHIZAL FUNGI FIGURE WO-6 Symbiotic relationship between plants and bacteria. Legume roots release compounds that trigger nitrogen-fixing rhizobia to express modified chitin oligomers called Nod factors, which in turn facilitate infection of the root by the bacteria, as well as New WO-6 nodule development.
From page 28...
... Parasites on plant roots include root-knot nematodes, nearly ubiquitous pathogens that account for up to 10 percent of global crop loss, according to Ané. Evidence suggests that these nematodes infect legume roots by using genetic pathways adapted for rhizobial colonization, perhaps by producing molecular mimics of Nod factors (Weerasinghe et al., 2005)
From page 29...
... (b) Only viable gram-negative vector type elements bitmap image w/bacteria form dense aggregations.
From page 30...
... well by moderating their virulence. Joshua Lederberg, "Infectious History" (2000)
From page 31...
... He noted Lederberg's long-standing concerns about the challenge posed by disease-producing microbes and discussed Lederberg's early work demonstrating the genetic basis for antimicrobial drug resistance. Many in attendance at this workshop, and certainly the scientists whose presentations are summarized herein, would echo the following remark by Falkow: "I consider all of the scientists whose discoveries expanded Lederberg's initial work on bacterial conjugation to be giants standing on his shoulders, and they made possible my own experimental work." The Nature of Bacterial Pathogenicity As Lederberg's observation above suggests, and studies of indigenous microbial communities attest, coexistence between host and microbe is a dynamic equilibrium (Blaser, 1997; Lederberg, 2000)
From page 32...
... "I submit that medicine's focus on disease really distracts us from understanding the biology of pathogenicity," he said. "Disease does not encompass the biological aspects of pathogenicity and the evolution of the host-parasite relationship." Thus, he continued, "If the nature of microbial pathogenicity is schizophrenic -- characterized by inconsistent or contradictory elements -- then it is important to study every aspect of its biology, and not be distracted by its role in causing disease." Microbial Virulence and the Host Response Just as there is more to microbial pathogenicity than disease, there is more to infectious disease than the actions of virulence factors on host cells and systems.
From page 33...
... But how to account, in evolutionary terms, for the disadvantages of host "immunoperversity": the tendency to overreact to pathogens, resulting in host morbidity and mortality? This phenomenon may be an artifact of the relative slowness of human evolution, Levin explained, coupled with the low efficiency of infectious disease-mediated selection in our species.
From page 34...
... typhi, however, this "stealth" strategy is essential to its survival. Workshop presentations described how evolution -- both ancient and recent -- has shaped pathogenicity in Salmonella, from its initial acquisition of genes that confer invasiveness to the loss of gene function in some serovars, leading to a reduction in host range and increasing virulence, to the recent challenge of antibiotics, which the bacterium has quickly met with resistance.
From page 35...
... , research by Parkhill and colleagues indicates that host-restricted, virulent pathogens such as S typhi have evolved those characteristics following a loss of function in genes that control interactions with host cells (thereby limiting their host range)
From page 36...
... pertussis and B parapertussis did not acquire novel virulence factors, but in stead lost function in genes associated with host interaction (thereby narrowing their host ranges)
From page 37...
... Perhaps these developments could have been anticipated based on Lederberg's work on bacterial conjugation, a key route by which plasmids carrying drugresistance genes are horizontally transferred between bacteria. Certainly, the ongoing impact of antibiotic resistance has confirmed the importance of understanding its evolutionary, genetic, and ecological origins, as several workshop presentations attested.
From page 38...
... Novel antibiotics are unlikely to be developed without significant financial incentives for the pharmaceutical industry, which has largely abandoned infectious disease therapeutic discovery for more profitable targets, such as chronic conditions (Spellberg et al., 2008)
From page 39...
... One compound they have discovered is a single enzyme possessing two antibiotic resistance domains: one that disables penicillin-like compounds; the other, cephalosporin-like compounds. Although never before seen, such an enzyme may someday find its way into the human microbiome (or microbial community)
From page 40...
... . Possible toxicity from the targeting of such host genes, which Cohen termed host-oriented therapeutics, must be addressed, he acknowledged -- just as they must for infectious disease therapies aimed at microbial targets.
From page 41...
... Having considered a wide spectrum of examples of microbial evolution and co-adaptation, and the diverse outcomes for microbes and hosts as individuals, species, and communities, workshop participants considered the global effects of host-microbe relationships that manifest as emerging infectious diseases. As defined by presenter Stephen S
From page 42...
... While more than half of emergent diseases can be attributed to antibiotic resistance, Daszak said, zoonoses -- infectious diseases that can be transmitted from vertebrate animals to humans -- have also increased significantly, particularly those 21 Familiardiseases that have recently expanded their geographic range and/or demonstrated intensified virulence due to such factors as reduced public health measures or antibiotic resistance.
From page 43...
... bitmap image SOURCE: Reprinted from Morens et al.
From page 44...
... and Microbial Threats to Health (IOM, 2003) , produced by ad hoc committees co-chaired by Lederberg, provided a crucial framework for understanding the drivers of infectious disease emergence.
From page 45...
... The in leading WO-12.eps bitmap image terior of the box is a gradient flowing from white to black; the white outer edges represent what is known about the factors in emergence, and the black center represents the unknown (similar to the theoretical construct of the "black box" with its unknown constituents and means of operation)
From page 46...
... . Environmental changes may also expand the geographic range occupied by species that serve as hosts or vectors for infectious diseases.
From page 47...
... The Origin of Novelty While anthropogenic factors provide plenty of fuel for infectious disease emergence, pathogens clearly can and do evolve, and at a far faster rate than do humans, as Lederberg (2000) observed.
From page 48...
... Perhaps the best known example of this sharing is horizontal gene transfer, which allows one organism to acquire genes encoding new functions from another. In addition, microbes greatly facilitate the acquisition of functions by "macrobes" such as plants and animals by engaging in symbiotic interactions.
From page 49...
... Concentrated in lower-latitude developing countries, these areas largely lack infectious disease surveillance and control efforts, which are disproportionately focused on the world's healthiest, wealthiest citizens. Thus, Daszak concluded, "we are misallocating our global efforts to deal with emerging infections." Our Wits Versus Their Genes Discussion at the workshop's conclusion (and immediately following the session on emerging infectious diseases)
From page 50...
... Copyright 2008. bitmap image landscape
From page 51...
... Additional efforts beyond those directed at improving surveillance strategies and technologies will be needed to alter a political climate in which descriptive surveillance programs have been dismissed as "stamp collecting" and a dearth of outbreaks and epidemics is interpreted as a reason to curtail "unnecessary" public health initiatives. Participants offered various strategies for educating policy makers and the public on such matters as the accelerating emergence of infectious diseases, the true cost of infectious disease in comparison to that of surveillance, and the costeffectiveness of broad-based surveillance for multiple infectious threats (e.g., zoonoses)
From page 52...
... Although the possibility of incentives for resource-poor countries has been raised, such a program has yet to be established. Even if the goal of global infectious disease surveillance is realized, however, another problem looms: how to interpret the ensuing flood of information.
From page 53...
... of disease. It also illustrates Lederberg's hopeful description of the present era of infectious history: "Together with wiser insight into the ground rules of pathogenic evolution, we are developing a versatile platform for developing new responses to infectious disease" (Lederberg, 2000)
From page 54...
... and Koch (ultimately a German professor of public health) -- that set a new course for studying and contending with infectious disease.
From page 55...
... Too small to be seen with the conventional microscope, these agents were described as "filtrable [sic] viruses." With a foundation of germ theory in place even before the 20th century, the study of infectious disease was ready to enter a new phase.
From page 56...
... .26 Similar trends are seen in most other industrialized countries, but the gains have been smaller in economically and socially depressed countries. Other statistics reveal that the decline in mortality ascribable to infectious disease accounted for almost all of the improvement in longevity up to 1950, when life expectancy had reached 68.
From page 57...
... As infectious diseases have assumed lower rankings in mortality statistics, other killers -- mostly diseases of old age, affluence, and civilization -- have moved up the ladder. Heart disease and cancer, for example, have loomed as larger threats over the past few decades.
From page 58...
... TABLE WO-1 An Infectious Disease Timeline 1300s 1346 Black Death begins spreading in Europe. 1400s 1492 Christopher Columbus initiates European-American contact, which leads to transmission of European diseases to the Americas and vice versa.
From page 59...
... 1860s Louis Pasteur concludes that infectious diseases are caused by living organisms called "germs." An early practical consequence was Joseph Lister's development of antisepsis by using carbolic acid to disinfect wounds. 1876 Robert Koch validates germ theory of disease and helps initiate the science of bacteriology with a paper pinpointing a bacterium as the cause of anthrax.
From page 60...
... 1979 Smallpox eradication program of WHO is completed; the world is declared free of smallpox. 1981 AIDS first identified as a new infectious disease by U.S.
From page 61...
... 1995 J Craig Venter, Hamilton Smith, Claire Fraser, and colleagues at The Institute for Genomic Research elucidate the first complete genome sequence of a microorganism: Haemophilus influenzae.
From page 62...
... After all, natural history points to analogous infections in simians that have long since achieved a mutually tolerable state of equilibrium. Costly experiences with AIDS and other infectious agents have led to widespread reexamination of our cohabitation with microbes.
From page 63...
... These multiple wake-up calls to the infectious disease problem have left marks in vital statistics. From mid-century to 1982, the U.S.
From page 64...
... One harbinger of the kind of high-tech wit we will need for defending against outbreaks of infectious disease is the use of cutting-edge communications technology and the Internet, which already have been harnessed to post prompt global alerts of emerging diseases (see osi.oracle.com:8080/promed/promed. home)
From page 65...
... That idea developed into the first concrete example of a hereditary adaptation to infectious disease. Haldane's theory preceded Anthony C
From page 66...
... Microbial zeal also can be self-defeating. As with rogue cancer cells, deviant microbial cells (such as aggressive variants from a
From page 67...
... Research into infectious diseases, including tuberculosis, schistosomiasis, and even AIDS, is providing evidence for this view. So are studies of Helicobacter, which has been found to secrete antibacterial peptides that inhibit other enteric infections.
From page 68...
... Together with wiser insight into the ground rules of pathogenic evolution, we are developing a versatile platform for developing new responses to infectious disease. Many new vaccines, antibiotics, and immune modulators will emerge from the growing wealth of genomic data.
From page 69...
... BOX WO-4 The Microbial World Wide Web The field of molecular genetics, which began in 1944 when DNA was proven to be the molecule of heredity in bacteria-based experiments, ushered microbes into the center of many biological investigations. Microbial systems now provide our most convenient models for experimental evolution.
From page 70...
... The scientific and humanistic rationale is self-evident: to enhance and apply scientific knowledge to manage infectious disease, naturally occurring or otherwise. Further Readings W
From page 71...
... Dolin, Principles and Practice of Infectious Diseases (Churchill Livingstone, 5th ed., Philadelphia, 2000)
From page 72...
... Emerging Infectious Diseases 7(3)
From page 73...
... 2008. Global trends in emerging infectious diseases.
From page 74...
... Clinical Infectious Diseases 46(2)
From page 75...
... 1998. Emerging and reemerging infectious diseases: a multidisciplinary perspective.


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