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Workshop Overview1 MICROBIAL EVOLUTION AND CO-ADAPTATION: A WORKSHOP IN HONOR OF JOSHUA LEDERBERG Prologue To a great extent, the Forum on Microbial Threats (hereinafter, the Forum) owes its very existence to the life and legacies of the late Dr. Joshua Lederberg. Dr. Lederberg’s death on February 2, 2008, marked the departure of a central figure of modern science. It is in his honor that the Forum hosted this public workshop on “microbial evolution and co-adaptation” on May 20 and 21, 2008. Along with the late Robert Shope and Stanley C. Oaks, Jr., Lederberg orga- nized and co-chaired the 1992 Institute of Medicine (IOM) study, Emerging Infections: Microbial Threats to Health in the United States (IOM, 1992). The Emerging Infections report helped to define the factors and dynamic relation- ships that lead to the emergence of infectious diseases. The recommendations of this report (IOM, 1992) addressed both the recognition of and interventions against emerging infections. This IOM report identified major unmet challenges in responding to infectious disease outbreaks and monitoring the prevalence of endemic diseases, and ultimately led to the Forum’s creation in 1996 (Morse, 2008). As the first chair of the Forum, 1996-2001, Dr. Lederberg was instrumen- tal in establishing it as a venue for the discussion and scrutiny of critical and sometimes contentiousscientific and policy issues of shared concern related to 1The Forum’s role was limited to planning the workshop, and this workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 

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 MICROBIAL EVOLUTION AND CO-ADAPTATION research on and the prevention, detection, and management of infectious diseases and dangerous pathogens. Lederberg’s influence may readily be appreciated in the 2005 Forum work- shop Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship (IOM, 2006a). Its central theme was derived from a comprehensive essay entitled “Infectious History” that he published several years earlier in Science (Lederberg, 2000; reprinted as Appendix WO-1). Under the heading, “Evolving Metaphors of Infection: Teach War No More,” Lederberg argued that “[w]e should think of each host and its parasites as a superorganism with the respective genomes yoked into a chimera of sorts.” Thus began a dis- cussion that developed the concept of the microbiome—a term Lederberg coined to denote the collective genome of an indigenous microbial community—as a forefront of scientific inquiry (Hooper and Gordon, 2001; Relman and Falkow, 2001). Having reviewed the shortcomings and consequences of the war metaphor of infection, Lederberg suggested, in the same essay, a “paradigm shift” in the way we collectively identify and think about the microbial world around us, replacing notions of aggression and conflict with a more ecologically—and evolutionarily—informed view of the dynamic relationships among and between microbes, hosts, and their environments (Lederberg, 2000). This perspective recognizes the participation of every eukaryotic organism—moreover, every eukaryotic cell—in partnerships with microbes and microbial communities, and acknowledges that microbes and their hosts are ultimately interdependent upon one another for survival. It also encourages the exploration and exploitation of these ecological relationships in order to increase agricultural productivity and to improve animal, human, and environmental health. The agenda of the present workshop demonstrates the extent to which con- ceptual and technological developments have, within a few short years, advanced our collective understanding of microbial genetics, microbial communities, and microbe-host-environment relationships. Through invited presentations and dis- cussions, 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 emer- gence 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.

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 WORKSHOP OVERVIEW Organization of the Workshop Summary This workshop summary was prepared for the Forum membership by the rapporteurs and includes a collection of individually authored papers 2 and com- mentary. Sections of the workshop summary not specifically attributed to an individual reflect the views of the rapporteurs and not those of the Forum on Microbial Threats, its sponsors, or the IOM. The contents of the unattributed sections are based on presentations and discussions at the workshop. The workshop summary is organized into chapters as a topic-by-topic sum- mation of the presentations and discussions that took place at the workshop. Its purpose is to present lessons from relevant experience, to delineate a range of pivotal issues and their respective problems, and to offer potential responses as discussed and described by workshop participants. Although this workshop summary provides an account of the individual presentations, it also reflects an important aspect of the Forum philosophy. The workshop functions as a dialogue among representatives from different sectors and allows them to present their beliefs about which areas may merit further attention. The reader should be aware, however, that the material presented here expresses the views and opinions of the individuals participating in the workshop and not the deliberations and conclusions of a formally constituted IOM study committee. 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. At the same time, this gathering was unique in the history of the Forum, for it also offered participants a chance to reflect upon Lederberg’s life (see Box WO-1) and his extraordinary contribu- tions to science, academia, public health, and government. Formal remarks by David Hamburg of Cornell University’s Weill Medical College, Stephen Morse of Columbia University, and Adel Mahmoud of Princeton University (collected in Chapter 1) inspired open discussion of Lederberg’s life and legacy, as well as personal reminiscences about his role as mentor, advisor, advocate, and friend. Recalling the words of Ralph Waldo Emerson, who likened institutions to the lengthened shadows of their founders (Emerson, 1841), Morse observed that Lederberg’s influential shadow reaches into many places, but is most imposing in 2 Some of the individually authored manuscripts may contain figures that have appeared in prior peer-reviewed publications. They are reprinted as originally published.

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 MICROBIAL EVOLUTION AND CO-ADAPTATION BOX WO-1 Joshua Lederberg: An Extraordinary Life • orn on May 23, 1925, in Montclair, New Jersey, to Zvi Lederberg, an orthodox B rabbi, and Esther Schulman, a homemaker and descendant of a long line of rabbinical scholars; Lederberg’s family moved to the Washington Heights area of upper Manhattan when he was six months old. • rom 1938-1940, attended Stuyvesant High School in New York City (a public, F highly competitive school of science and technology). • In 1941, enrolled at Columbia University, majoring in zoology. • n 1943, enrolled in the United States Navy’s V-12 training program, which I combined an accelerated premedical and medical curriculum to fulfill the armed services’ projected need for medical officers. • n 1944, received his bachelor’s degree in zoology at Columbia and began I medical training at the university’s College of Physicians and Surgeons. the area of infectious diseases, as epitomized by the Forum. Indeed, Forum mem- ber 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. As stated previously, it was largely due to Lederberg’s efforts, and particularly his co-chairmanship of the IOM Committee on Emerging Microbial Threats to Health, that the idea for a Forum became a reality. In recognition of the profound 3Vice-Chair from July 2001 to June 2004; Chair from August 2004 to July 2007.

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 WORKSHOP OVERVIEW • n 1946, during a year-long leave of absence from medical school, carried I out experiments on Escherichia coli in the laboratory of Edward Tatum at Yale University. Lederberg’s findings demonstrated that certain strains of bacteria can undergo a sexual stage, and that they mate and exchange genes. • n 1947, having extended his collaboration with Tatum for another year in order I to begin mapping the E. coli chromosome, received his Ph.D. degree from Yale. He then received an offer of an assistant professorship in genetics at the University of Wisconsin, which caused him to abandon his plans to return to medical school in order to pursue basic research in genetics. He was accom- panied by his new wife, Esther Zimmer Lederberg, who received her doctorate in microbiology at Wisconsin and who also rose to prominence in that field. • n 1957, founded and became chairman of the Department of Medical Genet- I ics at Wisconsin and was elected to the National Academy of Sciences. • n 1958, became the first chairman of the newly established Department I of Genetics at Stanford University’s School of Medicine, days before being awarded the Nobel Prize in Physiology or Medicine, along with Tatum and George Beadle, for “discoveries concerning genetic recombination and the organization of the genetic material of bacteria.” • n 1966, his marriage to Esther Lederberg ended in divorce; in 1968 he mar- I ried Marguerite Stein Kirsch, a clinical psychologist, with whom he had two children. • rom 1966-1971, published “Science and Man,” a weekly column on science, F society, and public policy in The Washington Post. • In 1978, accepted the presidency of Rockefeller University. • In 1989, awarded the National Medal of Science. • n 1990, retired from the presidency and continued at Rockefeller as Raymond I and Beverly Sackler Foundation Scholar. • In 2006, awarded the Presidential Medal of Freedom. • On February 2, 2008, died of pneumonia at New York-Presbyterian Hospital. SOURCE: NLM (2008); photo courtesy of The Rockefeller University. impact of Emerging Infections: Microbial Threats to Health in the United States (IOM, 1992)—which provided the U.S. 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 Preven- tion (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID) asked the IOM to create a forum to serve as a follow-on activity to the national disease strategy developed by these agencies. In 1996, the IOM launched the Forum on Emerging Infections (now the Forum on Microbial Threats). Lederberg chaired the Forum for its first five years and remained an avid participant in its workshops and discussions until his failing health precluded travel.

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 MICROBIAL EVOLUTION AND CO-ADAPTATION Even in his physical absence, the Forum has continued—and undoubtedly will continue—to be inspired by Lederberg’s expansive vision: a command of science that forged connections between microbiology and a broad range of disciplines, that was profoundly informed by history and literature, and that embraced the fullness of human imagination and possibility. Scientist “Joshua Lederberg has been the dominant force that shaped our thinking, responses, and intellectual understanding of microbes for much of the last half of the twentieth century,” Mahmoud remarked. 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. He also noted along with several other participants that the hero of the classic sci- ence fiction novel The Andromeda Strain4 (Crichton, 1969), Dr. Jeremy Stone, may well have been based on Lederberg. Ultimately, Lederberg viewed his wide- ranging scientific interests through the lens of evolution. According to Morse, the unifying theme of Lederberg’s scientific studies was to characterize sources of genetic diversity and natural selection. Nowhere is Lederberg’s comprehensive view of microbial evolution and its consequences more evident than in his essay, “Infectious History” (Lederberg, 2000), which informed the workshop’s agenda and serves as a framework for this workshop overview. Referring to that landmark publication as “the Bible of infectious diseases,” Mahmoud observed that it laid out “fundamental concepts that we are still debating about [including] the evolutionary biology and the ecol- ogy of microbes.” From his earliest years, Lederberg embodied scientific curiosity and innova- tion, David Hamburg noted. He recalled Lederberg’s knack for “turning an issue on its head, and thereby illuminating it,” and added that he “took deep, deep sat- isfaction in discovery, his own and others,” which was apparent in his relentless questioning. Lederberg “was a great challenger of the scientific community to pursue many ramifications of questions that appeared to be, at least for the time being, answered but were never answered for him,” Hamburg said. “This inter- 4 TheAndromeda Strain (1969), by Michael Crichton, is a techno-thriller novel documenting the efforts of a team of scientists investigating a deadly extraterrestrial microorganism that rapidly and fatally clots human blood. The infected show Ebola-like symptoms and die within two minutes (see http://en.wikipedia.org/wiki/The_Andromeda_Strain; accessed December 15, 2008).

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 WORKSHOP OVERVIEW related set of attributes characterized Josh all his life and had much to do with his great accomplishments.” Hamburg recounted that Lederberg entered medical school at Columbia University with this intense curiosity and sense of discovery, as well as a desire to improve the lot of humanity and to relieve human suffering. Fascinated with bacterial genetics, however, Lederberg took a one-year leave from medical school to work on Escherichia coli with Edward Tatum, at Yale University, in 1946. “This was groundbreaking, highly imaginative work on the nature of microorgan- isms, especially their mechanisms of inheritance,” Hamburg said. “It opened up bacterial genetics, including the momentous discovery of genetic recombination,” a line of inquiry that paved the way for Lederberg’s being awarded the Nobel Prize in Physiology or Medicine in 1958, along with Tatum and George Beadle for “discoveries concerning genetic recombination and the organization of the genetic material of bacteria.” Following an extremely successful first year of research in Tatum’s labo- ratory, Lederberg decided to take another year away from medical school and continue to explore bacterial genetics. “We lost the budding physician in Joshua Lederberg by the end of the second year, because he was offered a faculty posi- tion at the University of Wisconsin,” Mahmoud explained, “but that did not stop Joshua Lederberg from being at the forefront of those concerned about human health and well-being.” According to Forum member Jo Handelsman, professor of bacteriology at the University of Wisconsin, Lederberg’s influence reverberates to this day. “He left behind the great legacy of his research and the spirit of a truly great mind in science,” she said, as well as stories that have attained the status of “urban legends.” At Wisconsin, Lederberg also established the legendary habit of appearing to sleep during seminars, after which he would ask difficult and prob- ing questions. This habit was still in evidence in the early 1990s during his co- chairmanship of the first IOM study on emerging infections, according to Forum member Enriqueta (Queta) Bond, president of the Burroughs Wellcome Fund. “I was the executive officer at the Institute of Medicine when the first Emerging Infections report was done,” she recalled. “I remember coming to one of the first meetings of the committee, and . . . Josh would sit there and you would think, ‘Is he awake? He’s supposed to be chairing this committee.’ . . . Then you would get the zingers from Josh: just the perfect question to move the agenda, develop the next topic, and so forth.” Indeed, Morse said, Lederberg “was never happier than when he was absorb- ing knowledge and questioning it. I like to think of this, with all of us here, as being an important part of Josh’s legacy,” he added. Hamburg recalled Lederberg’s “rare capacity to range widely with open eyes and open mind, and also dig deeply at times into specialized topics; to combine these capacities in research, educa- tion, and intellectual synthesis led to so much fruitful stimulation in a variety of fields.”

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 MICROBIAL EVOLUTION AND CO-ADAPTATION “He believed that there are no limits to what the human mind can accom - plish, especially when its power is hitched to a willingness to think boldly and unconventionally, and to hard work,” Mahmoud said. “Until almost the day he died, Joshua could be found in his office, in his apartment, working. His mind was always thinking, always probing, always questioning.” Indeed, during his last days, Lederberg offered insightful advice to his longtime friend Hamburg, who was editing the final draft of his recently published book, Preventing Genocide: Practical Steps Toward Early Detection and Effective Action (Hamburg, 2008). “We had a couple of very intensive hours in which he asked his usual penetrat- ing questions and clarified key issues, and then was obviously quite exhausted,” Hamburg recalled. “We were prepared to take him back home. He said, ‘No. I’d like to rest for an hour or so and come back. I have one more chapter I want to discuss.’” “We did that,” Hamburg continued. “It was vintage Josh. He mobilized him- self to address an important problem with a friend that he valued and made an important contribution. The final changes in the book—all improvements—were due to that conversation.” Academic Another tribute to Lederberg’s remarkable capacities was institutional inno- vation, 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] genetics had been marginal or nonexistent in medical schools. There was a widely shared assumption, in the middle of the twentieth century, that genetics might be intrinsically interesting, but it would never have much practical significance for medicine.” “In teaching and in institution building, Lederberg emphasized the mutu- ally beneficial interplay of basic and clinical research,” Hamburg continued. Lederberg, he said, helped clinical departments at Stanford University’s School of Medicine build interdisciplinary groups and identify research opportunities and promising lines of innovation. He fostered many lines of inquiry within his own Department of Genetics at Stanford—including molecular genetics, cellu- lar genetics, clinical genetics, population genetics, immunology, neurobiology, and exobiology (particularly in relation to the National Aeronautics and Space Admininstration’s [NASA’s] Mariner and Viking missions to Mars)—and hired a superb group of internationally-known researchers, including Walter Bodmer and Eric Shooter from the United Kingdom, Luca Cavalli-Sforza from Italy, and Gus Nossal from Australia, Hamburg recalled. He also recruited from within the uni- versity, including speaker Stanley Cohen, who eventually succeeded Lederberg as chairman of the genetics department at Stanford. By taking this action, Hamburg said, Lederberg “was not robbing another department, but rather opening up an

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 WORKSHOP OVERVIEW opportunity that Stan [Cohen] wanted and needed, and, of course, in which he made tremendous contributions.” While at Stanford, Lederberg also made a major contribution to undergradu- ate education, establishing a cross-disciplinary program in human biology that remains one of the university’s most sought-after majors. Hamburg—who as chairman of Stanford’s psychiatry and behavioral science department, assisted in this effort along with Donald Kennedy, then the chairman of Stanford’s biol- ogy department—remarked that the program might not have had such a long and illustrious history if Lederberg had not insisted that it include endowed chairs. Following his years at Stanford, Lederberg’s “rich experience, knowledge, skill, and wisdom were brought to bear on Rockefeller University under his presidency, broadening the scope of its great faculty, opening new opportunities for young people, and greatly improving the facilities,” Hamburg said. Although admitting that he did not at first think university administration was the best use of his friend’s talents, Hamburg recognized that Lederberg adapted well to his new responsibilities and proved adept both as a financial and a human resources manager who was deeply concerned about the personal well-being of his faculty. While it seems that nothing was too big for Lederberg to tackle, Forum mem- ber Gerald Keusch of Boston University described how he had benefited from Lederberg’s willingness to address what might have seemed a small issue. Dur- ing the mid-1990s, National Institutes of Health (NIH) director Harold Varmus was thinking about the impact on NIH of shrinking the number of institutes and centers, beginning with the Fogarty International Center. “Harold is a very smart person and knew there were going to be problems in trying to change the status quo. How to proceed? You form a committee to give you the recommendation that allows you to go ahead and act,” Keusch recalled. “So he asked Josh and Barry Bloom5 to do a review of the Fogarty and all international programs at the NIH.” Lederberg and Bloom proceeded to conduct an exhaustive study, which ultimately recommended that the Fogarty be strengthened, not disbanded. As a result, a new position was created—for which Keusch was hired—to direct the Fogarty International Center and serve as the NIH’s associate director for inter- national research. After five years in this position, Keusch asked Lederberg and Bloom to return and review the Fogarty’s progress. Although unwell and not traveling as he once had, Lederberg did not hesitate “to come back to do an honest, objective review and [once again] come out strongly in favor of the Fogarty’s international mission,” Keusch said. “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/.

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0 MICROBIAL EVOLUTION AND CO-ADAPTATION international programs at NIH would not have attracted [Lederberg’s] attention. But they did, and I think the Fogarty is certainly the better for it, [as] is NIH.” Global Citizen Achieving the Nobel Prize at the age of 33 gave Lederberg a global per- spective that he fully embraced in the subsequent half-century, according to Mahmoud. In so doing, Lederberg undertook multiple roles, including advisor to governments, institutions, and industry, as well as educator of the general public. “Every president from John F. Kennedy to the current administration sought Joshua’s advice and consultation,” Hamburg said. “He chaired and studied issues from space science to human and artificial intelligence, to human-microbe inter- play.” Lederberg advised many agencies in the United States, most notably the NIH, the Centers for Disease Control and Prevention (CDC), the National Sci- ence Foundations (NSF), NASA, the Office of Science and Technology Policy (OSTP), and the Department of the Navy. He also served as an advisor to the World Health Organization (WHO) and was particularly influential as that orga- nization attempted to establish regional surveillance centers for emerging infec- tious 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. Hiroshi Nakajima. I am sure this is one of the reasons that WHO went on to develop its emerging infections focus.” “Josh used to go to Washington sometimes three times a week, back and forth, to give scientific advice,” Morse recalled. “He was the model of the sci- entific adviser. His advice was honest and dispassionate and in no way self- interested. His interest was furthering the cause of science and humanity.” Morse observed Lederberg had been concerned that samples obtained from space or spaceships might contain extraterrestrial life forms. NASA asked Lederberg how to decontaminate such samples and what precautions should be taken with them. “He gave very freely of his advice,” Morse said. “This led, I think, to one of the most interesting job descriptions I have ever seen. NASA created a position called ‘planetary quarantine officer.’6 Those of us who talk about emerging infections on this world have to realize that Josh’s purview extended far beyond that.” Emerging infections on Earth did, however, feature prominently in Lederberg’s advisory efforts, as many participants readily acknowledged. According to Mah- moud, “It was Josh, and Josh alone, who articulated and brought to the forefront of the scientific agenda the subject of emerging and reemerging infections.” Concern about emerging infections has grown following the appearance of new diseases, such as HIV/AIDS, and the reemergence of others, such as dengue, 6This position was later renamed by NASA as “Planetary Protection Officer, Earth.”

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 WORKSHOP OVERVIEW and from appreciation of the complex determinants of their emergence—including microbial adaptation to new hosts (HIV infection, severe acute respiratory syn- drome [SARS]), population immunity pressures (influenza A), travel (acute hemorrhagic conjunctivitis), animal migration and movement (West Nile virus infection, H5N1 avian influenza), microbial escape from antibiotic pressures (multidrug-resistant and extensively drug-resistant tuberculosis), mechanical dis- persal (Legionnaires’ disease), and others (panel, Figure WO-1; Morens et al., 2008).7 Lederberg was also “a pioneer in biological warfare and bioterrorism defense, applying his farsighted vision to efforts to understand the danger and find ways to cope with it,” Morse said, long before that threat was widely acknowledged. “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 . . . [and also] forced the whole community to come back, in 2003, for the second report on the sub- ject.” Lederberg also co-chaired the committee that produced this second report, Microbial Threats to Health (IOM, 2003), along with current Forum co-chair, Margaret (“Peggy”) A. Hamburg of the Nuclear Threat Initiative/Global Health and Security Initiative (and daughter of David Hamburg). At an early conference on emerging viruses, in 1989, “somebody asked Josh, when should we declare that a virus is a new species or a new unknown virus?” Morse recalled, to which Lederberg gave the Solomonic answer, “When it matters.” “That was very much Josh’s way, to cut through all of the red tape and all of the inconsistencies and see straight to the heart of the matter,” Morse concluded. Lederberg strongly believed in educating the public about science and encour- aging public discussion of complex and politically and emotionally charged top- ics, Peggy Hamburg said. The tangible evidence of this belief can be found in the columns on science and society that Lederberg wrote for The Washington Post between 1966 and 1971, and that have been collected by the National Library of Medicine at its website, “Profiles in Science” (NLM, 2008). As David Hamburg remembered, “many in the scientific community thought, why would a person of his gifts devote that kind of time to the public?” Lederberg believed, however, 7 For more information, see also IOM (1992, 2003); Morens et al. (2004); Parrish et al. (2008); and Stephens et al. (1998). 8The Convention on the Prohibition of the Development, Production and Stockpiling of Bacterio- logical (Biological) and Toxin Weapons and on their Destruction; signed on April 10, 1972; effective March 26, 1975. As of July 2008, there were 162 states party to this international treaty to prohibit an entire class of weapons.

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 WORKSHOP OVERVIEW the 19th century, Koch was convinced that rigorous experiments would support the doctrine of monomorphism: that each disease was caused by a single invari- ant microbial species rather than by the many that often showed up in culture. He argued that most purported “variants” were probably alien bacteria that had floated into the petri dishes from the atmosphere. Koch’s rigor was an essential riposte to careless claims of interconvertibility— for example, that yeasts could be converted into bacteria. It also helped untangle confusing claims of complex morphogenesis and life cycles among common bac- teria. But strict monomorphism was too rigid, and even Koch eventually relented, admitting the possibility of some intrinsic variation rather than contamination. Still, for him and his contemporaries, variation remained a phenomenological and experimental nuisance rather than the essence of microbes’ competence as pathogens. The multitude of isolable species was confusing enough to the epi- demic tracker; it would have been almost too much to bear to have to cope with constantly emerging variants with altered serological specificity, host affinity, or virulence. Even today it would be near heresy to balk at the identification of the great plague of the 14th century with today’s Yersinia pestis; but we cannot readily account for its pneumonic transmission without guessing at some intrinsic adap- tation at the time to aerosol conveyance. Exhumations of ancient remains might still furnish DNA evidence to test such ideas. We now know and accept that evolutionary processes elicit changes in the genotypes of germs and of their hosts. The idea that infection might play an important role in natural selection sank in after 1949 when John B. S. Haldane conjectured that the prevalence of hemoglobin disorders in Mediterranean peoples might be a defense against malaria. That idea developed into the first concrete example of a hereditary adaptation to infectious disease. Haldane’s theory preceded Anthony C. Allison’s report of the protective effect of heterozygous hemoglobinopathy against falciparum malaria in Africa. The side effects of this bit of natural genetic engineering are well known: When this beneficial polymorphism is driven to higher gene frequencies, the homozy- gous variant becomes more prevalent and with it the heavy human and societal burden of sickle cell disease. We now have a handful of illustrations of the connection between infection and evolution. Most are connected to malaria and tuberculosis, which are so prevalent that genetic adaptations capable of checking them have been strongly selected. The same prevalence also makes their associated adaptations more obvious to researchers. A newly reported link between infection and evolution is the effect of a ccr (chemokine receptor) deletion, a genetic alteration that affords some protection against AIDS. It would be interesting to know what factors—another pathogen perhaps—may have driven that polymorphism in ear- lier human history. One lesson to be gleaned from this coevolutionary dynamic is how fitful and

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 MICROBIAL EVOLUTION AND CO-ADAPTATION sporadic human evolution is when our slow and plodding genetic change is pitted against the far more rapidly changing genomes of microbial pathogens. We have inherited a robust immune system, but little has changed since its early vertebrate origins 200 million years ago. In its inner workings, immunity is a Darwinian struggle: a randomly generated diversification of leukocytes that collectively are prepared to duel with a lifetime of unpredictable invaders. But these duels take place in the host soma; successful immunological encounters do not become genetically inscribed and passed on to future generations of the host. By contrast, the germs that win the battles quickly proliferate their successful genes, and they can use those enhancements to go on to new hosts, at least in the short run. The human race evidently has withstood the pathogenic challenges encoun- tered so far, albeit with episodes of incalculable tragedy. But the rules of encoun- ter and engagement have been changing; the same record of survival may not necessarily hold for the future. If our collective immune systems fail to keep pace with microbial innovations in the altered contexts we have created, we will have to rely still more on our wits. Evolving Metaphors of Infection: Teach War No More New strategies and tactics for countering pathogens will be uncovered by finding and exploiting innovations that evolved within other species in defense against infection. But our most sophisticated leap would be to drop the man- ichaean view of microbes—“We good; they evil.” Microbes indeed have a knack for making us ill, killing us, and even recycling our remains to the geosphere. But in the long run microbes have a shared interest in their hosts’ survival: A dead host is a dead end for most invaders too. Domesticating the host is the better long-term strategy for pathogens. We should think of each host and its parasites as a superorganism with the respective genomes yoked into a chimera of sorts. The power of this sociological development could not be more persuasively illustrated than by the case of mito- chondria, the most successful of all microbes. They reside inside every eukaryote cell (from yeast to protozoa to multicellular organisms), in which they provide the machinery of oxidative metabolism. Other bacteria have taken similar routes into plant cells and evolved there into chloroplasts—the primary harvesters of solar energy, which drive the production of oxygen and the fixed carbon that nourishes the rest of the biosphere. These cases reveal how far collaboration between hosts and infecting microbes can go. In the short run, however, the infected host is in fact at metastable equi- librium: The balance could tip toward favorable or catastrophic outcomes. On the bad side, the host’s immune response may be excessive, with autoim- mune injuries as side effects. Microbial zeal also can be self-defeating. As with rogue cancer cells, deviant microbial cells (such as aggressive variants from a

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 WORKSHOP OVERVIEW gentler parent population) may overtake and kill the host, thereby fomenting their own demise and that of the parent population. Most successful parasites travel a middle path. It helps for them to have aggressive means of entering the body surfaces and radiating some local toxicity to counter the hosts’ defenses, but once established they also do themselves (and their hosts) well by moderating their virulence. Better understanding of this balancing act awaits further research. And that may take a shift in priorities. For one, research has focused on hypervirulence. Studies into the physiology of homeostatic balance in the infected host qua superorganism have lagged. Yet the latter studies may be even more revealing, as the burden of mutualistic adaptation falls largely on the shoulders of the para- site, not the host. This lopsided responsibility follows from the vastly different evolutionary paces of the two. But then we have our wits, it is to be hoped, for drafting the last word. To that end, we also need more sophisticated experimental models of infec- tion, which today are largely based on contrived zoonoses (the migration of a parasite from its traditional host into another species). The test organism is usu- ally a mouse, and the procedure is intended to mimic the human disease process. Instead, it is often a caricature. Injected with a few bugs, the mouse goes belly up the next day. This is superb for in vivo testing of an antibiotic, but it bears little relation to the dynamics of everyday human disease. Natural zoonoses also can have many different outcomes. In most cases, there will be no infection at all or only mild ones such as the gut ache caused by many Salmonella enteritidis species. Those relatively few infectious agents that cause serious sickness or death are actually maladapted to their hosts, to which they may have only recently gained access through some genetic, environmental, or sociological change. These devastatingly virulent zoonoses include psittacosis, Q fever, rickettsiosis, and hantavirus. Partly through lack of prior coevolutionary development with the new host, normal restraints fail. I suggest that a successful parasite (one that will be able to remain infec- tious for a long time) tends to display just those epitopes (antigen fragments that stimulate the immune system) as will provoke host responses that (a) moderate but do not extinguish the primary infection, and (b) inhibit other infections by competing strains of the same species or of other species. According to this speculative framework, the symptoms of influenza evolved as they have in part to ward off other viral infections. Research into infectious diseases, including tuberculosis, schistosomiasis, and even AIDS, is providing evidence for this view. So are studies of Helico- bacter, which has been found to secrete antibacterial peptides that inhibit other enteric infections. We need also to look more closely at earlier stages of chronic infection and search for cross-protective factors by which microbes engage one another. HIV, for one, ultimately fails from the microbial perspective when

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 MICROBIAL EVOLUTION AND CO-ADAPTATION opportunistic infections supervene to kill its host. That result, which is tragic from the human point of view, is a byproduct of the virus’s protracted duel with the host’s cellular immune system. The HIV envelope and those of related viruses also produce antimicrobials, although their significance for the natural history of disease remains unknown. Now genomics is entering the picture. Within the past decade, the genomes of many microbes have been completely sequenced. New evidence for the web of genetic interchange is permeating the evolutionary charts. The functional analyses of innumerable genes now emerging are an unexplored mine of new therapeutic targets. It has already shown many intricate intertwinings of hosts’ and parasites’ physiological pathways. 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. The lessons of HIV and other emerging infections also have begun taking hold in government and in commercial circles, where the market opportunities these threats offer have invigorated the biotechnology industry. If we do the hard work and never take success for granted (as we did for a while during the last century), we may be able to preempt infectious disasters such as the influenza outbreak of 1918-1919 and the more recent and ongoing HIV pandemic. Perhaps one of the most important changes we can make is to supercede the 20th-century metaphor of war for describing the relationship between people and infectious agents. A more ecologically informed metaphor, which includes the germs’-eye view of infection, might be more fruitful. Consider that microbes occupy all of our body surfaces. Besides the disease-engendering colonizers of our skin, gut, and mucous membranes, we are host to a poorly cataloged ensem- ble of symbionts to which we pay scant attention. Yet they are equally part of the superorganism genome with which we engage the rest of the biosphere. The protective role of our own microbial flora is attested to by the superinfec- tions that often attend specific antibiotic therapy: The temporary decimation of our home-team microbes provides entrée for competitors. Understanding these phenomena affords openings for our advantage, akin to the ultimate exploitation by Dubos and Selman Waksman of intermicrobial competition in the soil for seeking early antibiotics. Research into the microbial ecology of our own bodies will undoubtedly yield similar fruit. Replacing the war metaphor with an ecological one may bear on other impor- tant issues, including debates about eradicating pathogens such as smallpox and polio. Without a clear strategy for sustaining some level of immunity, it makes sense to maintain lab stocks of these and related agents to guard against possible recrudescence. An ecological perspective also suggests other ways of achieving lasting security. For example, domestication of commensal microbes that bear relevant cross-reacting epitopes could afford the same protection as vaccines based on the virulent forms. There might even be a nutraceutical angle: These

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 WORKSHOP OVERVIEW commensal epitopes could be offered as optional genetically engineered food additives, clearly labeled and meticulously studied. Another relevant issue that can be recast in an ecological model is the rise in popularity of antibacterial products. This is driven by the popular idea that a superhygienic environment is better than one with germs—the “enemy” in the war metaphor. But too much antibacterial zeal could wipe out the very immuno- genic stimulation that has enabled us to cohabit with microbes in the first place. 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. Diverse mechanisms for genetic variation and recombination uncovered in such systems are spelled out in ponderous monographs. Assays for chemical mutagenesis (e.g., the Ames test using Salmonella) are now routinely carried out on bacteria, because microbial DNA is so accessible to environmental insult. Mutators (genes that enhance variability) abound and may be switched on and off by different environmental factors. The germs’ ability to transfer their own genetic scripts, via processes such as plasmid transfer, means they can exchange biological innovations including resistance to antibiotics. Indeed, the microbial biosphere can be thought of as a World Wide Web of informational exchange, with DNA serving as the packets of data going every which way. The analogy isn’t entirely superficial. Many viruses can integrate (download) own DNA into host genomes, which subsequently can be copied and passed on: Hundreds of segments of human DNA originated from historical encounters with retroviruses whose genetic information became integrated into our own genomes. What makes microbial evolution particularly intriguing, and worrisome, is a combination of vast populations and intense fluctuations in those populations. It’s a formula for top-speed evolution. Microbial populations may fluctuate by factors of 10 billion on a daily cycle as they move between hosts, or as they encounter antibiotics, antibodies, or other natural hazards. A simple comparison of the pace of evolution between microbes and their multicellular hosts suggests a million fold or billion fold advantage to the microbe. A year in the life of bacteria would easily match the span of mammalian evolution! By that metric, we would seem to be playing out of our evolutionary league. Indeed, there’s evidence of sporadic species extinctions in natural history, and our own human history has been punctuated by catastrophic plagues. Yet we are still here! Maintaining that status within new contexts in which germs and hosts inter- act in new ways almost certainly will require us to bring ever more sophisticated technical wit and social intelligence to the contest. -J. L.

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0 MICROBIAL EVOLUTION AND CO-ADAPTATION Ironically, even as I advocate this shift from a war metaphor to an ecology metaphor, war in its historic sense is making that more difficult. The darker corner of microbiological research is the abyss of maliciously designed biologi- cal warfare (BW) agents and systems to deliver them. What a nightmare for the next millennium! What’s worse, for the near future, technology is likely to favor offensive BW weaponry, because defenses will have to cope with a broad range of microbial threats that can be collected today or designed tomorrow. As a measure of social intelligence and policy, we should push for enforce- ment of the 1975 BW disarmament convention. The treaty forbids the devel- opment, production, stockpiling, and use of biological weapons under any circumstances. One of its articles also provides for the international sharing of biotechnology for peaceful purposes. 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. Bulloch, History of Bacteriology (Oxford University Press, London, 1938). R. Dubos, Mirage of Health: Utopias, Progress, and Biological Change (Rutgers University Press, New Brunswick, New Jersey, 1987). J. Lederberg, R. E. Shope, S. C. Oaks Jr., Eds., Emerging Infections: Microbial Threats to Health in the United States (National Academy Press, Washington, D.C., 1992) (see www.nap.edu/books/0309047412/html/index.html). G. Rosen, A History of Public Health (Johns Hopkins University Press, Balti- more, 1993). T. D. Brock, The Emergence of Bacterial Genetics (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1990). S. S. Morse, Ed., Emerging Viruses (Oxford University Press, New York, 1993). Journal of the American Medical Association theme issue on emerging infections, August 1996. W. K. Joklik et al., Eds., Microbiology, a Centenary Perspective (ASM Press, Herndon, Virginia, 1999). S. C. Stearns, Ed., Evolution in Health and Disease (Oxford University Press, Oxford, New York, 1999). P. Ewald, “Evolution of Infectious Disease,” in Encyclopedia of Microbiology, J. Lederberg, Ed. (Academic Press, Orlando, Florida, 2000).

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