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1 The Life and Legacies of Joshua Lederberg OVERVIEW The essays in this chapter offer three personal perspectives on Joshua Lederberg’s many contributions to science, society, scholarship, and to the lives and careers of his colleagues, students, and friends. The first contributor, David A. Hamburg of Cornell University’s Weill Medical College, recounts Lederberg’s legacies as scientist and humanist through the lens of nearly 50 years of friend- ship. In the second essay, Stephen S. Morse, of Columbia University, recalls meeting Lederberg, who was then president of Rockefeller University, when Morse was “the most junior of junior faculty members.” Thus began a friendship, rooted in a shared interest in emerging infectious diseases, that lasted for more than 20 years—a collaboration that embraced the ideas upon which the Forum on Microbial Threats was founded. Former Forum chair Adel Mahmoud, of Princeton University, notes in the chapter’s final essay that “this Forum is the brainchild of Joshua as he was explor- ing how to respond to the multifaceted challenges of microbes.” After reviewing and celebrating the breadth of his accomplishments, Mahmoud concludes that Lederberg “needs no monument to ensure that his life and work are long remem- bered.” Rather, his ideas and example will continue to be “an inspiration and a reminder that our work can truly change the world just as the life and career of Joshua Lederberg certainly did.” 

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG REFLECTIONS ON THE CAREER OF JOSHUA LEDERBERG David A. Hamburg, M.D.1 Carnegie Corporation I am honored to speak about Josh Lederberg on the occasion of this important meeting. It was my great privilege to have nearly half a century of joint efforts and deep friendship with him. Let me start with a citation for his achievements written three decades after he received his Nobel Prize in Medicine. In 1989, our nation’s highest honor in science and technology, the National Medal of Science, was awarded to him with a concise and illuminating citation: For [Joshua Lederberg’s] work in bacterial genetics and immune cell single type antibody production; for his seminal research in artificial intelligence in biochemistry and medicine; and for his extensive advisory role in government, industry, and international organizations that address themselves to the societal role of science. I could add more—and will, to some extent. All of us here respect his truly great scientific achievements and creative leadership in science and public policy. How did all of this happen? In childhood, he had prodigious intellectual gifts, along with a reverence for learning and scholarship—powerfully reinforced by his family. From then on, his life was characterized by boundless curiosity—a fresh look at everything. He took deep satisfaction in discovery—and then raising the next question, and the next, and challenging the scientific community to pursue many ramifica- tions. This interrelated set of attributes characterized him all his life and had much to do with his great accomplishments. One dramatic feature of his career: he was a school dropout—medical school, that is. He entered medical school with his typical intense curiosity and sense of discovery. This was a learning moment: the emergence of the new biology. He shifted to graduate school in biology to pursue the frontiers of knowledge. There began a line of inquiry that led before long to the Nobel Prize. This was groundbreaking, highly imaginative work on the nature of micro- organisms, especially their mechanisms of inheritance. He opened up bacterial genetics, including the momentous discovery of genetic recombination. This work was one of the crucial foundations for subsequent discoveries in cellular and molecular biology. Many of us stood on his shoulders. He won the Nobel Prize in 1958 at the age of 33—one of the youngest winners in any field from any nation. Another attribute was his remarkable capacity for institutional innovation. 1 President emeritus.

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 MICROBIAL EVOLUTION AND CO-ADAPTATION He created a department of genetics in the medical school at Stanford University. Until then, 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 that it would never have much practical significance for medicine. How wrong that assumption was! While actively stimulating and fostering basic research, Josh also sought applications, and he helped to create the biotechnology industry. In teaching and in institution building, he emphasized the mutually beneficial interplay of basic and clinical research. In this context, he was very generous in helping to establish new clinical departments and new kinds of clinical departments. At Stanford, he helped with psychiatry, pediatrics, medicine, and neurology. He inspired us with the classic experiments of Oswald Avery, Colin MacLeod, and Maclyn McCarty at Rock- efeller University in the 1940s. Their clinical inquiry into pneumonia led to a great discovery on the most basic level: DNA is the genetic material. He helped us to build on basic components and to create interdisciplinary groups. He also helped us to identify research opportunities and promising lines of innovation. He was a wide-ranging mentor. The world is full of people grateful to Josh for his powerful insights, creative suggestions, and generosity of spirit. Within his own remarkable department at Stanford, he fostered many lines of inquiry: molecular genetics, cellular genetics, clinical genetics, population genet- ics, exobiology (the National Aeronautics and Space Administration’s [NASA’s] Mariner and Viking missions to Mars), immunology, and neurobiology. He always had a worldwide view and brought in superb people, not only from the mysterious east of the United States, like New York City, but also, for example, Walter Bodmer (United Kingdom), Luca Cavalli-Sforza (Italy), Gus Nossal (Australia), Eric Shooter (United Kingdom), and others from afar—all of whom were major contributors. His global outlook, long-term vision, intense curiosity, and unfailing kindness inspired all of us seeking to create new kinds of clinical departments. Moreover, he did much to strengthen the scientific capabil- ity of the World Health Organization (WHO). Thus, his rare capacity to range widely with open eyes and an open mind— and also to dig deeply into a specialized topic, and to combine these capacities in research, education, and intellectual synthesis—led to fruitful stimulation in a variety of fields and nations. His knowledge, curiosity, and imagination have been expressed in many ways. For example, he was instrumental in the creation of a highly innovative undergraduate major at Stanford, now past its thirty-fifth year as one of the most sought after majors at Stanford, drawing in faculty from across the university. It is broadly integrative across the life sciences, linking basic science, hands-on experience (including field research), biological aspects of behavioral science, and in the senior year, applications of the life sciences to policy (e.g., in health

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG and environmental problems). He even found a way to make this a permanent program by insisting that we find a way to get endowed chairs. Early in the computer era his interest in computer science grew and he became a pioneer in artificial intelligence, especially in relation to biochemistry, genetics, and medicine. He believed deeply in education of the broad public, opening complex and emotionally charged topics for informed public discussion. One major vehicle was a column in The Washington Post during the 1970s, in which he interpreted science for the public and for several years produced fascinating, highly informa- tive columns. He was a pioneer in the scientific assessment of the human impact on the environment—and especially on the health implications of environmental conditions. All of this rich experience, knowledge, skill, and wisdom were brought to bear on Rockefeller University under his presidency, where he broadened the scope of its great faculty, opened new opportunities for young people, and greatly improved the facilities. His deep respect and concern for the well-being of faculty—young and not so young—was remarkable. This was a crucial aspect of his leadership. Josh was a pioneer in biological warfare and bioterrorism, applying his far- sighted vision in efforts to understand the danger and find ways to cope with it. He strongly influenced the negotiation of the biological weapons disarmament treaty. He advised the U.S. government in many agencies, including: the National Institutes of Health (NIH), the National Science Foundation (NSF), NASA, the Navy Office of Science and Technology Policy (OSTP), the Department of Energy, the Defense Science Board, and others. So too on the world stage. In addition, his deep sense of science’s contributions to the well-being of humanity was expressed in his role as co-chair of the Carnegie Commission on Science, Technology, and Government, producing multiple publications on most branches of government, strengthening their science and technology capacities and their decision-making processes. He served with distinction on the National Acad- emies’ Committee on International Security and Arms Control (CISAC), heading its efforts in biology. Altogether, I know of no eminent scientist who produced so much serious analysis of public policy and social problems, giving wise advice and stimulating new lines of inquiry. Our country and the world are in his debt. Those of us here today profoundly appreciate what he did for humanity. His life exemplified the finest attributes of the great institution in which we meet today, and we honor his magnificent legacy.

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0 MICROBIAL EVOLUTION AND CO-ADAPTATION JOSH LEDERBERG REMEMBERED Stephen S. Morse, Ph.D.2 Columbia University Josh would have loved this meeting. He loved this institution. He loved the Forum on Microbial Threats and the efforts that preceded it. I keep looking around the room thinking that Josh has got to be here some- where. He is, in a very real sense. It was Ralph Waldo Emerson, I think, who said that an institution is the lengthened shadow of a man—well, in those days he would have said “man,” but today we would say “person.” In many ways, Josh’s shadow was a very long one, indeed. I think we are all very much in his debt. It’s especially humbling to follow David Hamburg and to be in a room where many of the people—and I see several here—knew Josh far longer and far better than I did. During the discussion period, I hope they’ll add their own thoughts, which are sure to be very valuable and instructive. I said it’s humbling to follow David Hamburg on the podium. Let me give a small anecdote to illustrate what I mean. After Josh retired as president, the Rockefeller University gave him an office suite and lab, of course. His outer office was basically a library—this was very much in Josh’s character—with rows and rows of files, books, and journals on just about every subject you can imagine. That was the outer office. His ever-loyal administrative assistant, Mary Jane Zimmermann—some people referred to her as Josh’s gatekeeper during his days at the Rockefeller University, but personally I always found her benevolent, and very considerate—had a desk there as well, in this library-like outer office, which was not quite the size of this meeting room. He had several of his many awards displayed next to the door in this outer office, but when you went into his private inner office, he had only three things on the wall, as I recall. He had a certificate as a ham radio operator (apparently he was very proud of that) and his certificate as a fellow of the American Academy of Microbiology—and a picture of David Hamburg! All the other things were in the outer office, but this showed what Josh kept close to his heart. Everybody has spoken, of course, of Josh’s unique and indisputable greatness as a scientist and his interests in many areas that I think we can only touch on. He began or pioneered in many fields. Those of us who worry about emerging infections in this world, and feel that’s really challenging, came to realize how far beyond even that Josh’s purview extended. David Hamburg mentioned Josh’s starting the field of exobiology, a term that he himself coined. There are even many people who think (although I haven’t gone back to verify this) that the hero in The Andromeda Strain (Crichton, 1969) was based on Josh Lederberg. 2 Professor of epidemiology and founding director of the Center for Public Health Preparedness at the Mailman School of Public Health.

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG It wouldn’t surprise me. In any case, some years ago, the National Aeronautics and Space Administration (NASA) had asked him for advice on how to properly decontaminate returning spaceships and samples sent back from space, on what precautions should be taken. As you know, he always gave very generously of his time and advice. This led to one of the most interesting job descriptions I have ever seen. After receiving Josh’s advice, NASA created a position called “planetary quarantine officer.” I always thought that was quite impressive, rather like the film Men in Black. Apparently, however, unlike in the film, they were fortunately never called upon to exercise their functions. Josh’s interest in evolution, of course, has been mentioned many times. On one occasion, Josh mentioned to me that he saw the unifying theme of his sci- ence: the sources of genetic diversity (and natural selection, I’d add). I think this was apparent in many ways. It was apparent in his work in microbiology, but it was also apparent in his interest in immunology, as David mentioned in passing. Josh went down to Australia, where he met Mac Burnet, Sir Frank Macfarlane Burnet, later to win the Nobel Prize for his work on “clonal selection,” which we now know is how the immune system is able to recognize and respond to the great variety of molecules that it does. The developing immune system generates a great number of cells with different, essentially random specificities and then selects from among them and maintains these populations of cells, the “immu- nologic repertoire.” When a new antigen is presented, immune cells can bind to the antigen attach and are stimulated to replicate, hence, “clonal selection.” It is basically a Darwinian system that selects from among a large number of variant cells. That idea of clonal selection, Josh told me, was actually a direct applica- tion of the evolutionary ideas that Josh brought with him and worked on when he was in Australia. So his shadow—indeed, his presence—can be found in many places, and no place, of course, more than in the area of infectious diseases. That’s why I think this particular meeting would have made him very happy, to see so many of his old friends, and particularly to see so many of the fruits of his hard work. I think all of us—and this certainly applied to Josh—do the things we do in the hope of leaving the world a better place and leaving something that will inspire future generations to keep improving the world. So this meeting, with scientists of several generations describing their work that was started by some of Josh’s interests, is very much a testament to Josh’s legacy. Unlike David, I had the pleasure of knowing Josh for only a little more than 20 years. When I came to Rockefeller, Josh was the minence grise (a role he car- ried as well as he had his earlier one of child prodigy, becoming a Nobel Laureate at age 33), the president of Rockefeller, and the distinguished Nobel laureate; and I was among the most junior of junior faculty members. (I eventually worked myself up to being a more senior junior faculty member.) It was actually just by a happy coincidence that Josh and I got involved in this issue of emerging infections. I went to a faculty party that was given periodically

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 MICROBIAL EVOLUTION AND CO-ADAPTATION at the president’s house. Just as I was leaving, Josh’s wife, Marguerite, who is also a psychiatrist—maybe it’s just a coincidence, but now that I know from David Hamburg’s background, I have a feeling Josh had a special affinity for psychiatrists—reminded Josh about something he had wanted to do. She said, “Sweetheart, didn’t you have some questions about virology? Steve’s a virolo- gist, you know.” Josh said, “Oh, yes.” It turns out that he had had dinner with Carleton Gajdusek. Many of you may remember Gajdusek (and, sadly, his later legal problems), but he was also a very innovative and brilliant scientist himself, with many interesting ideas. He was very interested in the hemorrhagic fever viruses, such as the hantaviruses, and discovered Prospect Hill virus, the first American hantavirus. At that dinner, he was talking with Josh and suggested he should think about the researchers and workers in the university’s animal facilities, who might be exposed to a hantavirus such as Seoul or Hantaan (once known as Korean hemorrhagic fever), which had been a known problem. There were schoolchildren in Russia who had contracted a hantavirus from laboratory rats while touring the animal facilities on a school trip. Obviously, Carleton, in his usual forceful man- ner, had succeeded in getting Josh concerned about it. So Josh asked me that evening if this was something we should worry about. I replied, “I’ll look into it.” So, of course, I went and looked into it. It turned out that it wasn’t a problem for us, I was relieved to find. Not only did we not have any cases of disease, but all our rodents were routinely tested. I wrote my reply to Josh’s question in a letter dated February 17, 1988, saying “I enjoyed our conversation about Korean hemorrhagic fever and other emerging viruses,” thinking of those viruses and mechanisms of pathogenesis not yet identified in humans but known to exist in other species. Josh wrote back quickly, on his personal notepaper—and here I must digress for a moment. Everybody who has received a note from Josh knows these are not to be compared with Donald Rumsfeld’s now famous “snowflakes”: Josh’s were much more substantial. I know it’s a digression, but Josh’s wonderful notes deserve a digression. All of Josh’s colleagues and friends know that Josh had a personal notepad with his name in light blue at the top, and that the notes were always date-stamped. There were also some markings, like hieroglyphics at the top or bottom—a check mark with two dots, or an “x” with three dots; Mary Jane once sent me a chart that explained these meant things like, “Keep copy in files” or “Send a copy and retain original.” I don’t know if he had that habit at Stanford. To return to the narrative: Josh wrote me a note in his usual magisterial style, date-stamped February 22, which said “Thank you for the information, which I read with great interest. I am of course reassured. . . . We need some high-level policy attention to what needs to be done globally to deal with the threat of emerging viruses, and I would welcome your thoughts on that.”

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG Naturally, not knowing any better, and only knowing Josh slightly at that time, I took that as a call to action. Shortly thereafter, at a Federation of Ameri- can Societies for Experimental Biology (FASEB) meeting, I ran into Gaylen Bradley, a former postdoc of Josh’s from his Wisconsin days, who had also been my department head when I was a postdoc (he has recently written his own bio- graphical memoir of Josh). I asked Gaylen for advice on how to respond to this oracular statement. The obvious conclusion was to have some sort of conference to deal with this question of emerging viruses. Some colleagues (I recall particularly Sheldon Cohen, now retired from the NIH) sent me to John LaMontagne at the National Institute of Allergy and Infectious Diseases (NIAID), who was very sympathetic and said he had similar interests. We organized a conference under NIAID’s auspices, held on May 1, 1989, at the Hotel Washington (Washington, DC). We could afford it then because it was undergoing major renovations, as everybody who ever stayed there during that period for the conference knew, since they could hear the renovations going on. We got a very good rate. I know that because I never could afford to stay there afterwards. In this big ballroom, we had perhaps 150 people, with a number of distin- guished speakers on various subjects (and an equally distinguished audience). Of course, Josh was very much the star of the meeting. He opened it with a keynote address and participated in discussions at the end of the meeting. There was a summary of that meeting, for those who are interested, in the Journal of Infec- tious Diseases in 1990, and then in my book, Emerging Viruses, which was sort of a by-product of that meeting. Josh gave very thoughtful and philosophical opening remarks, of course. One thing about Josh that never failed to surprise me was that he would say things that were truly gems, often profound, and they wouldn’t strike you until days later, when suddenly you realized what he meant by that. It was an “aha” experience, in many ways like the joy of a scientific discovery. I always enjoyed seeing the reactions of people having this experience for the first time. One year, I was fortunate enough to have him address my Colum- bia graduate class in emerging infectious diseases, as the grand finale for the semester. He talked about the toll of the 1918 influenza pandemic, its effect on life expectancy curves, and many other things. By then, I was familiar with Josh’s often very philosophical and discursive style. The students listened to Josh and mostly looked very pensive. I suspect that most of the students were probably mystified by parts of his talk, but many were stimulated days, weeks, or even months later, when one of his comments hit them, and they were inspired to take some of those thoughts and pursue them. Josh was very good at inspiring people. He had a special gift for that. In terms of mentorship, he cared deeply about the people he worked with. He was passionate about the many issues with which he was concerned, none more than the threat of microbes, perhaps, or as he summarized the situation in an article,

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 MICROBIAL EVOLUTION AND CO-ADAPTATION “Our Wits Versus Their Genes” (Lederberg, 2000). Their genes have been evolv- ing a lot longer than our wits, I needn’t tell you. In another paper he made the analogy to bacteriophage infecting a dense culture of bacteria in a tube of broth and how suddenly—and this was a classic observation—the tube became clear. That was in a Journal of the American Medical Association (JAMA) article that he wrote, in which he used the term “humankind” in the title. (Josh was not a sexist.) Ruth Bulger, who was then director of the Board on Health Policy, and Polly Harrison, who was director of the Board on Global Health at the Institute of Medicine (IOM), came along to the 1989 meeting, and we had several discus- sions together. This helped to galvanize the IOM into doing a study that Josh had been advocating for some time. The study committee, which was originally the Committee on Microbial Threats to Health but which was rather quickly renamed the Committee on Emerging Microbial Threats to Health in the United States, eventually authored the famous report, Emerging Infections: Microbial Threats to Health in the United States that came out in October 1992. Several of you who are here today were on that Committee. As you know, the report has become a clas- sic and, I am told, one of the IOM’s best-sellers of all time. By the way, Richard Preston had an article in the New Yorker that was timed to coincide with the release of the report. The article was later expanded into the book The Hot Zone (Preston, 1995). More recently, Peggy Hamburg and Josh co-chaired a 10-year reappraisal, the report of which I think is destined to become another classic. The report called for better infectious disease surveillance, a better under- standing of pathogenesis, and a better understanding, in fact, of many, many things, including the political will to deal with emerging infections. Science was one of Josh’s real passions. As David Hamburg pointed out, no matter how sick Josh may have been in his later days, whenever the talk turned to science, he was all ears. His eyes would light up and he would be eager to take in all of that knowledge—and, of course, ask probing and often very informative questions. Josh had a knack for putting together words in wonderful ways and a knack for asking the right questions—often very profound questions. I think it was absolutely remarkable the way he combined those two talents. I’ll give an example or two later. He also had a passion for scientific advice and scientific policy, for which he gave of himself selflessly. I would always bump into him on the Delta shuttle or at a meeting such as this one, or many others, and he was always shuttling back and forth between New York and Washington. I knew he went many times to Wash- ington. However, it wasn’t until an eightieth birthday party for Josh that Richard Danzig and other friends organized at the Academy building that I realized—in fact, Marguerite told us—that Josh used to go to Washington sometimes three times a week, back and forth, to give scientific advice. He was the very model of the perfect scientific adviser. His advice was honest, dispassionate, and never self-interested. His interest was furthering the cause of science and humanity. He

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG was always the soul of discretion as well. I think that policy and technical advice were things that those of us of a certain period—Josh’s period, certainly—felt was a civic obligation. More and more, this has become a highly politicized process, but Josh could always be depended upon to give honest advice and ask good questions. That belated eightieth birthday party was, I believe, the penultimate time he went to Washington. The last trip to Washington was when he went to pick up the Presidential Medal of Freedom (which, I recently discovered, David had also received earlier). Josh was deservedly very proud of that recognition. He had earned it. I mentioned Josh’s unique way with words. As I said earlier, I used to see him often at various meetings. Once we were invited to a World Health Organiza- tion (WHO) meeting, and bumped into each other before the meeting at a hotel that the WHO then used quite regularly, the Cornavin—some of you may know it—right by the train station in Geneva. I had just registered and Josh walked in, shook my hand, and said, “My, my, we always meet in the most expected places”—just one small example. Back at that 1989 conference on emerging viruses, Josh was also a star of the show. There were several other Nobel laureates there, including my old friend and former professor Howard Temin. Josh and Howard had a very interesting debate, which unfortunately was not officially recorded, but as I recall, it cer- tainly induced a lot of adrenaline. Later, somebody asked Josh, “When should we declare that a newly recognized virus is a new species?” He said, “When it matters.” I quoted this to my wife, who was duly impressed, and said, “What a Solomonic answer!” That was very much Josh’s way; to cut through all the red tape and all the inconsistencies and see straight to the heart of the matter, to distinguish what was really important and what was not. Before I close (and I fear I’ve already taken up more than my space quota), I think I should say a few words about the early history of the Forum on Microbial Threats, or, as it was then known, the Forum on Emerging Infections. A number of you in the room probably already know this history. Of course, it started just the way that David showed in that slide of the Sistine Chapel ceiling. However, the Institute of Medicine did not at that time have quite so palatial surroundings. After the Committee on Microbial Threats and publica- tion of its final report, many of us thought about what a possible follow-on could be. It’s often said that American lives have no second act. Certainly, the report was a very hard act to follow, but there was recognition of a need to continue the momentum and advance the dialogue. After much deliberation, which included Josh and the then-president of the Institute of Medicine, Sam Thier, who was a great supporter of this effort, Polly Harrison, Ruth Bulger, as well as myself, Polly and Ruth suggested that it would be appropriate to start a forum that could bring together people from—I won’t say all walks of life, but from academe,

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 MICROBIAL EVOLUTION AND CO-ADAPTATION industry, and from the government, to talk about these issues. As you know, Josh was delighted to chair this. The very first issue that the Forum on Emerging Infections discussed was something very close to Josh’s heart: vaccine capacity for microbial threats. It led to our first report, Orphans and Incentives, which set out the problem and suggested some alternatives. The rest of what happened after that, of course, is history. It was very much Josh’s energy that made it possible and remains a key part of Josh’s legacy. A second thing that happened subsequent to publication of the report was that several of us who were concerned about the international ramifications of emerging infections decided to start the Program for Monitoring Emerging Dis- eases (ProMED) to plan and promote global surveillance of infectious diseases, especially emerging pathogens. In fact, it was the late Bob Shope, who was co- chair of that original IOM committee with Josh, who came up with that name just off the top of his head. Jim Hughes, Ruth Berkelman, and D. A. Henderson, along with a number of others, were charter members of the steering committee. One of the most successful spin-offs of the ProMED initiative is well known to those of you who get the e-mails from ProMED-mail or read its website. 3 Josh was never officially a member, because I thought it might be a little too political, and I didn’t want to put him in an awkward position. I always kept him in the loop unofficially, and he was a great supporter of the effort, later publicly as well as privately. But I can’t help thinking that part of the reason that Josh was such a great fan of ProMED-mail may have been that it was an e-mail system, and Josh was glad to see e-mail used to bring people together for a crucial and worthy purpose. In fact, Josh was one of the earliest adopters of e-mail I know of. In those days, e-mail was almost impossible to use. You had to do all the formatting and editing of the message by hand, line by line, and send it using a 1,200 baud modem by dial-up. We had nothing more than that. I remember how technologi- cally advanced I felt when I finally got a 2,400 baud model. So I had not learned to use e-mail because it required such a lot of effort and there was a steep learning curve. Josh once looked at me and said, “You really should use e-mail, you know.” I replied it was just too much trouble, adding “I don’t even have a modem.” He shamed me into it. He said, in his very typical fashion, “That’s no problem. I’ll buy you a modem.” I did have enough grant money at the time to buy myself a modem. It was from that inspiration that, in fact, ProMED-mail was later born. So Josh really can take the credit for starting many things, including that initiative. I will add, in closing, that Josh served very happily as president of the Rock- efeller University. The trustees loved him. He was one of their real favorites. I know this because I did a trustees’ dinner with him on emerging infections. Of 3 See www.promedmail.org.

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG course, he was the star of the show, and I was sort of the appendage. What a star to be the appendage for! I owe a great deal to Josh in many other ways as well. My time at the Defense Advanced Research Projects Agency (DARPA) from 1996 to 2000 was because Josh convinced the people at DARPA (especially its director at the time, Larry Lynn) that it was necessary to get into biology and seriously consider biological threats. He asked me if I would be interested in his nominating me for a job there. It was one of the most interesting chapters of my own career and, I have to say, an exceptional place to work that was committed to finding creative new ideas. I hope we managed to fund and stimulate a few. (David Relman was one of the grantees, for work on gene expression profiling in infections.) At the time one of our concepts was to look at common pathways of patho- genesis (Stan Falkow will remember his invaluable advice on this), as well as the host response and possible host markers of infection. The rationale was fairly simple: there was a tremendous number of pathogens, in addition to whatever was lurking unrecognized out there in nature, plus the possibility of genetically engi- neered threats in the future. Approaching the threats individually (what some of my colleagues called “one bug—one drug”) would become impossible. Later, this idea would be embodied in Homeland Security Presidential Directive (HSPD)-18 and other current biodefense initiatives. We really owe all these ideas to Josh’s vision in making us all think much more globally. At the Rockefeller University, he was, as I mentioned, very influential as president, although after he stepped down I saw him on campus looking very relaxed and wearing a Rockefeller baseball cap. I need not tell you that his office as president had floor-to-ceiling bookshelves crammed with books, but there was another room down the hall in the same building. Those of you who know the Rockefeller will know it as the Cohn Library. It was in a public area and was sometimes used as a conference room. It, too, was filled with books. One day I was waiting there for a meeting to start and idly began browsing some of the books on the shelves. I discovered that many of them were stamped with Josh’s name. He had donated them to the library. After he stepped down as president and had his own office, in deference to his many interests and skills—he could not include them all—he named his laboratory the Laboratory of Molecular Genetics and Bioinformatics, emphasiz- ing the relationship of the two. I think that was the first time those terms had been coupled, or at least the first time I had seen them together. He had always been a great supporter of both, as well as a great innovator in both of these fields. I hope this brief account gives some indication not only of how much a poly- math he was but also how deeply he cared about people and science. I remember talking later with Torsten Wiesel, another Nobel laureate, after he became presi- dent of Rockefeller. He said, “You know, Josh was lucky. He got his Nobel Prize early so he could spend the rest of his life doing what he wanted.”

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 MICROBIAL EVOLUTION AND CO-ADAPTATION What Josh wanted to do was to search for truth and inspire others in that search, for the benefit of humankind. He was never happier than when he was absorbing knowledge and questioning it. I like to think of this inspiration, with all of us here because of Josh, as his greatest legacy. THE LIFE AND IMPACT OF A LEGEND—JOSHUA LEDERBERG Adel Mahmoud, M.D., Ph.D.4 Princeton University It is fitting to dedicate this workshop of the Forum on Microbial Threats (hereinafter, the Forum) to Joshua Lederberg and to a subject that was central to his thinking of the past decade. This Forum is the brainchild of Joshua as he was exploring how to respond to the multifaceted challenges of microbes. Those of us old enough will remem- ber that the Forum was Joshua’s response to the first Emerging Infections report of the Institute of Medicine (IOM) in 1992. Joshua opened the preface to that volume as follows: As the human immunodeficiency virus (HIV) disease pandemic surely should have taught us, in the context of infectious diseases, there is nowhere in the world from which we are remote and no one from whom we are disconnected. Consequently, some infectious diseases that now affect people in other parts of the world represent potential threats to the United States because of global interdependence, modern transportation, trade, and changing social and cultural patterns. He felt as if he always guided us; that the issues of infectious disease at hand will not go away and that a platform for academia, government, industry, and oth- ers to study, debate, and chart a path forward was necessary. It was my privilege and honor to have succeeded Josh as chair of the Forum. I am not here today to talk about the Forum, and I will only touch briefly on the subject matter of our meeting. Rather, I am participating in a celebration of the life and achievements of Dr. Lederberg. One can simply state that Joshua Lederberg has been the dominant force that shaped our thinking, response, and intellectual understanding of microbes for much of the second half of the twentieth century. Infectious Disease Research From his earliest work when, at the age of just 20, he discovered mating and genetic recombination in Escherichia coli, to the discovery of viral transduction 4Woodrow Wilson School of Public and International Affairs and the Department of Molecular Biology, Lewis Thomas Laboratory, Room 228, Princeton, NJ 08544.

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG in bacteria, Joshua Lederberg helped to establish the new science of genetic engineering and its fundamental contribution to the study of infectious disease. There is a lot to share with you about these early days of Josh’s career. Most of the fundamental breakthrough research on bacterial mating was performed while he was on leave from Columbia University’s College of Physicians and Surgeons. When the great results of his early studies were clearly opening new horizons, he decided to extend his leave of absence from medical school for another year. That was where we lost the budding physician in Joshua; during the subsequent year, he was offered a faculty position at the University of Wisconsin, where he conducted his seminal work on viral transduction in bacteria. But that did not stop Joshua Lederberg from being at the forefront of those concerned about human health and well-being as we witnessed his leadership over the past several decades. The “Stanford years” witnessed the maturation of the field of bacterial genetics and the expansion of Joshua’s scientific horizon to areas that touched upon human health and human biology. Equally important was his role in under- graduate and graduate education. The human biology curriculum was one distinct product of that era that Joshua championed. Joshua, the Leader Being awarded the Nobel Prize at the age of 33 gave Joshua a global per- spective that he fully utilized in the subsequent half century. His platform became the nation and the world, and his reach and impact touched every corner. A few examples illustrate this point. 1. Joshua the science educator: From presidents to the global public, Joshua consulted and advised every president since John F. Kennedy. He explored and studied issues ranging from space sciences to human and artificial intelligence to the human-microbial interplay. 2. Joshua the communicator: Few may still remember that Joshua contrib- uted a weekly science column to The Washington Post in an attempt to reach the general public and make science accessible. 3. Joshua the visionary: Equally important were his vision and his ability to conceptualize for the nation and the scientific community. I was fortunate to have worked closely with Josh on the subject that it was he and he alone who articulated and brought to the forefront of scientific agendas (i.e., emerging infections). In the late 1980s, the concept of emerging and reemerging infections was born by Joshua’s insistence that it get attention. The result is 25 years of focus that gave us two IOM reports (IOM, 1992, 2003), multiple plans from the Centers for Disease Control and Preven- tion (CDC), NIH, WHO, and our Forum. More importantly, global events proved how right and perceptive Joshua was then and now. Infections such

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0 MICROBIAL EVOLUTION AND CO-ADAPTATION as hantavirus pulmonary syndrome, severe acute respiratory syndrome (SARS), H5N1 avian influenza, and multidrug-resistant Staphylococcus aureus (MRSA) are all global events that shape the world today and will shape it for years to come. Perhaps, the most dominant feature of Joshua’s scientific contributions over the last three decades is articulating a vision for understanding human-microbe interplay with the dimensions that for many years remained fragmentary. An ecological and evolutionary understanding of that relationship emerged in mul- tiple publications and produced several revolutionary concepts. The introductory statement of an article written by Joshua a decade ago sums it up (Lederberg, 1998): Our relationship to infectious pathogens is part of an evolutionary drama. Here we are; here are the bugs. They are looking for food; we are their meat. How do we compete? They reproduce so quickly, and there are so many of them. They tolerate vast fluctuations of population size as part of their natural history; a fluctuation of 1 percent in our population size is a major catastrophe. Microbes have enormous potential mechanisms of genetic diversity. We are different from them in every respect. Their numbers, rapid fluctuations, and amenability to genetic change give them tools for adaptation that far outpace what we can generate on any short-term basis. So why are we still here? With very rare exceptions, our microbial adversaries have a shared interest in our survival. With very few exceptions (none among the viruses, a few among the bacteria, perhaps the clostridial spore-forming toxin producers), almost any pathogen reaches a dead end when its host is dead. Truly severe host-pathogen interactions historically have resulted in elimination of both species. We are the contingent survivors of such encounters because of this shared interest. In a subsequent masterpiece published in the journal Science in 2000, Joshua added the elements of a rational understanding of what we are as superorgan- isms and that the microbiota constitute the total interface between humans and microbes (Lederberg, 2000). That article also points to the futility of the “war metaphor” and proposes a more fundamental, nuanced, approach: As our awareness of the microbial environment has intensified, important ques- tions have emerged. What puts us at risk? What precautions can and should we be taking? Are we more or less vulnerable to infectious agents today than in the past? What are the origins of pathogenesis? And how can we use deeper knowledge to develop better medical and public health strategies? Conversely, how much more can the natural history of disease teach us about fundamental biological and evolutionary mechanisms? An axiomatic starting point for further progress is the simple recognition that humans, animals, plants, and microbes are cohabitants of the planet. That leads

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG to refined questions that focus on the origin and dynamics of instabilities within this context of cohabitation. These instabilities arise from two main sources loosely definable as ecological and evolutionary. Ecological instabilities arise from the ways we alter the physical and biologi- cal environment, the microbial and animal tenants (humans included) of these environments, and our interactions (including hygienic and therapeutic inter- ventions) with the parasites. The future of humanity and microbes likely will unfold as episodes of a suspense thriller that could be titled Our Wits Versus Their Genes. His mind never stopped analyzing and deeply exploring what comes next. An example of this comes from his article “Metaphysical Games: An Imaginary Lecture on Crafting Earth’s Biological Future” (Lederberg, 2005): A vector of traits can be plucked from natural sources, or constructed with pres- ent or proximate future bioengineering tools [see Box 1-1]. Taken without ques- tion is the ultimate capacity to craft altered and hybrid genomes—“knockouts,” “knockins,” “knockdowns and knockups,” and “shuffles.” Augmenting these constructions is the deconstruction of what is disappointing, what does not work as predicted. Mock or denounce, but get the arguments into the open for the feasibility and utility of constructing or domesticating a target candidate. At some point, there will be exhilaration or unease about the policy fallout, and col- leagues will be consulted about the best avenues for technology assessment. A Perspective Summation Joshua was a discoverer, a leader, and a champion in the truest and best sense of the words. His perceptiveness and impact had a fully positive effect on mankind and on history. Joshua was truly a force of nature, a force of nature that was able to unlock some of nature’s most enduring secrets. Joshua believed that there are no limits to what the human mind can accomplish—especially when its power is hitched to a willingness to think boldly and unconventionally and to hard work. Until almost the day he died, Joshua could be found in his office, in his apart- ment, working. His mind was always thinking, always probing, always question- ing. He has always been and will always be an inspiration to generations among us and generations to come. Thinking back to my own upbringing in Egypt, the constructions of monu- ments such as the Great Sphinx and the pyramids at Giza likely grew out of the enormous egos of the rulers who had them constructed. These rulers wanted to be sure that long after they were gone, people would be able to gaze upon their mighty works and remember that a great man once ruled here. Joshua Lederberg, of course, needs no such monuments to ensure that his life and work are long remembered, because, in a very real sense, his accomplish-

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 MICROBIAL EVOLUTION AND CO-ADAPTATION BOX 1-1 Traits That Could Be the Foundation of Selection in Unfamiliar Genomic Settings Fecundity: This is the fundamental measure of Malthusian fitness. Is obviously the most complex of traits, and rarely given fully unhampered play except in natu- ral or near-natural populations. It may also be entangled with efficiencies of diet, infection, and social arrangements. The race is not always to the swift, paradoxical selection sometimes favors a slower growing contender, with antibiotics that are more effective on bugs that have lowered their guard during the most rapid growth. What is the fastest-growing microbe? Perhaps a cousin of Vibrio natriegens, with a doubling time of less than 15 minutes. Life span: Research in this part of the matrix is well filled in yeast, roundworms, fruit flies, mice, birds—for these species constitute a large part of the research agenda of the National Institute of Aging. Chemical secretion, defense, detection, virulence, or disease susceptibility: What substance? What toxin? What function? Recall that secondary metabolism comprises a large part of contemporary applied microbiology. Desiccation: Survival and growth capacity of cells at reduced chemical activity of water. This is closely connected with anabiosis and dormancy with explicit or tacit spore formation. Large investments by the National Aeronautics and Space Administration are wrapped up with this issue because it is generally argued that the surface environment of Mars is incompatible with proliferation of terrestrial microbes. Depending on process details, the process of lyophilization may be toxic or preservative. Additives like trehalose mitigate the toxicity of the lyophilization process and may be emulated by other genetically engineered antifreeze under extensive investigation. Persistence of viable bacteria in aerosols is a critical point for a biological weapons attack. Motor: Power and discriminatory skills; motility some specialized cells. Some flagella are imputed to rotate at 50,000 rpm! ments are embedded in the DNA of many whose lives have been shaped because of his work. That work and those concepts will be passed on to every generation yet to come, long after the Great Sphinx has crumbled into dust. Joshua believed very strongly in the work of this Forum. He had a 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.

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 THE LIFE AND LEGACIES OF JOSHUA LEDERBERG Flight, marine, navigation kinetic fragility/tenacity: One aspect testable with acoustic energy in environment. Converse, more limited range in animals but what is loudest emission, doubtless related to animal size. For smaller targets this is tested by aerosolization. Thermal-susceptibility: Easily assayed, and heat/cold shock responses are under study. Thermal emission and absorption: Should be secondary to metabolic rates. Tropisms: To any part of EM [electromagnetic] spectrum: what are ultimate limits to sensitivity of detection? Vision-spatial acuity: Image formation at any wavelength. Energy emissions: May carry acoustic signals. Luminescence may be acousti- cally modulated, detected. Integration of signal inputs—IQ: It involves coordinated social action. As an outrageous question, “What could be measured, say in a bacterium, that could map to what might be called ‘intelligence’?” Geno-stability and pheno-stability (or instability); promiscuity: This trait may be related to survivability of laboratory cultures, to maintenance of strain charac- teristics, to production of variants as objects of selection, and to ease of research protocols. Genome size: An interesting trait in itself; related to “junk DNA.” Currency of lateral gene transfer: Bears on management of genetic change. SOURCE: Reprinted from Lederberg (2005) with permission from the American Medical As- sociation. Copyright 2005. By remembering him with this tribute we also are remembering the many things that his life and career can teach all of us. I hope, every time we meet at this Forum, Joshua Lederberg will be an inspi- ration and a reminder that our work can truly change the world, just as the life and career of Joshua Lederberg certainly did.

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 MICROBIAL EVOLUTION AND CO-ADAPTATION REFERENCES Morse References Crichton, M. 1969. The andromeda strain. New York: Knopf. Lederberg, J. 2000. Infectious history. Science 288(5464):287-293. Preston, R. 1995. The hot zone. First Anchor Books Ed. New York: Random House, Inc. Mahmoud References IOM (Institute of Medicine). 1992. Emerging infections: microbial threats to health in the United States. Washington, DC: National Academy Press. ———. 2003. Microbial threats to health: emergence, detection and response. Washington, DC: The National Academies Press. Lederberg, J. 1998. Emerging infections: an evolutionary perspective. Emerging Infectious Diseases 4(3):366-371. ———. 2000. Infectious history. Science 288(5464):287-293. ———. 2005. Metaphysical games: an imaginary lecture on crafting earth’s biological future. Jour- nal of the American Medical Association 294(11):1415-1417.