Genes, Germs and Medicine

The following sections are included:

• Dedication
• Acknowledgments
• Preface
• Contents

Joshua Lederberg’s contemporaries knew him to be one of the greatest scientists of the twentieth century, a creative mastermind, “a universal genius” — brilliant biologist, mathematician, computer scientist, statesman, philosopher, historian, and writer.2 It’s been said that the word polymath was invented for him. His “home field” was genetics, for which he was awarded the Nobel Prize, but he also made fundamental contributions to immunology, evolutionary theory, the search for extraterrestrial life, molecular medicine, biological engineering, artificial intelligence, and the study of emergent viral diseases…

Joshua was the first of three sons born to Esther (née Goldenbaum) and Zvi Lederberg, an orthodox rabbi, both natives of Yafo Palestine. There was a long line of religious Polish Jews on his father’s side who had emigrated to the Holy-Land. The tradition of rabbinical scholarship was even stronger on his mother’s side. Hers was a Hassidic rabbinical family from the town of Safed in the north of present day Israel. Her father, Rabbi Aharon Goldenbaum, was a member of Israel’s ultraorthodox Gur Hassidic sect. When the Turks began hunting for him before the First World War, he fled to America where he was appointed Rabbi of the Roumanian-American Synagogue in Brooklyn…

Lederberg considered several universities for the fall of 1941. He applied to Cornell in Ithaca but failed to receive a needed scholarship for tuition, room, and board because, he suspected, he was Jewish. “Cornell was quite discriminatory,” he later recalled, “a farm boy could get into the program I had in mind, I couldn’t.” Very few New York City students could. He considered City College of New York, which was downtown and he could stay at home and commute. A lot of brilliant students went there. But it was crowded and had limited laboratory facilities, so he considered it a last resort…

Lederberg had the field to himself when he set out to demonstrate genetic recombination in bacteria. Bacteria had been well studied as pathogens since Louis Pasteur and Robert Koch established the germ theory of disease in the 19^th century. But bacteria had not been studied from a genetics point of view. To understand why, we need to pause for a moment and understand the place of bacteria in the biological concepts of the time…

Lederberg had his work cut out for him when he returned from the Cold Spring Harbor Symposium to Tatum’s laboratory in the summer of 1946. He needed more data — more recombinants affecting more traits in bacteria. On October 19, 1946, Lederberg and Tatum sent a preliminary short note to Nature titled “Gene Recombination in Escherichia coli” to stake their claim. The reaction to their announcement was mixed. Some, like George Beadle, saw it as the most important advance in microbiology since the development of the germ theory of disease. “The story on the sex life of bacteria sounds darned exciting,” he wrote to Tatum in September 9, 1946. “It looks to me like it is the most important advance in bacteriology in the last hundred years. Congratulations”…

On April 30, 1947, Tatum received a letter from Alexander Brink, Chair of the Genetics Department at the University of Wisconsin, who was looking to hire someone who worked on the genetics of microorganisms. Tatum had completed his PhD in biochemistry at Wisconsin thirteen years earlier and knew the scene well. “Can you suggest anyone whom we might consider for the post?” Brink elaborated: General interest in genetics of microorganisms, is of course, too recent to have attracted many students in this direction. We realize that consequently there is a very narrow field from which to draw… The position is primarily in research, although as the work develops there might be a call for some class room teaching… we would want a man who could work effectively with certain other departments on the campus such as Agricultural Bacteriology, Plant Pathology and Biochemistry. …

The genetics building in the College of Agriculture looked like an over-grown log cabin, and when Lederberg arrived at Madison during the fall of 1947, his laboratory was a small 20 × 30-foot room in the basement. The university remodeled a new laboratory of about the same size for him by the spring of 1949. It was on the second floor right under the eaves and crowded with glassware, autoclaving and media preparation equipment, and a few benches. Laboratory space was just not that important for experimental breeding, which was the main focus of the genetics department then. As most of that work was in the field, their laboratory was outdoors…

Understanding bacterial sex was not easy as it differs starkly from that in plants and animals. There are no gametes that fuse to produce fertilized eggs. During bacterial conjugation, genes are transferred in a unidirectional fashion from donor cell to recipient cell. But all bacterial cells are not able to transmit genes this way. Only those that carry a “fertility factor” (F⁺) have this ability. F⁺ bacteria can transfer genes to another bacterium that lacks the fertility factor, but even then, they only transmit some of their genes, not all of them…

Leading evolutionary theorists had come to a consensus about evolutionary processes by mid century: evolution was considered to be a gradual process, fueled by gene mutations and recombination within species. Natural selection acted on minute hereditary variations within populations. Every species has a well-defined boundary, just as the individuals that comprise them have a single well-defined genome…

Lederberg’s research interests had advanced far beyond bacterial genetics per se by the late 1950s as he turned to address fundamental questions in mammalian immunology. No one knew how immunity worked: how the immune system produces a specific antibody in response to a specific infection invading the body. When a person gets sick with the flu, for example, their body produces specific antibodies to fight the invading pathogen. That is, a certain immunoglobulin molecule appears in the blood and binds to and inactivates a particular pathogen…

Sputnik was launched on October 4, 1957. Lederberg saw it in the sky over Melbourne. He knew that the space race would soon begin and that military interests and propaganda would over-shadow proper scientific exploration, especially in the search for extraterrestrial life and cosmic evolution. He got the US National Academy of Sciences involved in helping to shape space policy by establishing committees with leading scientists throughout the United States, and he moved NASA to launch a new field that he called exobiology…

Lederberg was becoming restless after ten years at Madison. If some members of the genetics department at the University of Wisconsin had had concerns about hiring him in 1947 (Chapter 6), a decade later the problem was reversed — they now had concerns that he would leave. The abrasive personality that his colleagues experienced when he was a graduate student had softened. His influence on campus was important, not only for the development of the genetics department, but for biology as a whole. As the Chair of the genetics department, Alexander Brink, recalled, “he had many of the characteristics of a genius and was just bursting with mental and physical energy”…

The contretemps at Berkeley was over by mid-March 1958, but fortunately, Lederberg had kept several balls in the air. In fact, he was already in the midst of finalizing negotiations with the medical school at Stanford University — the perfect fit, as it turned out. Actually, he had been offered a position in the biology department of Stanford in 1956; he and Esther had gone there for a visit during the winter of 1957, but he was not keen on the position or the university…

It was a frantic Autumn. The Lederbergs had spent four months away in Australia, India, and Europe. They had made their way past the Berkeley debacle and were preparing to move to Stanford early in the new year. Then, on Sunday, October 26, things got really complicated. Josh went to the lab alone around 11 am to work on two grant applications. At around 11:30, he received a call from a Swedish reporter who leaked the news that he, along with George Beadle and Edward Tatum, were to be co-recipients of the Nobel Prize in medicine. The announcement was going to be made on Thursday. He did not keep a diary in those days, but he decided to take notes on this event…

The Lederbergs landed in a whole new world when they moved to California in February 1959. It was the beginning of what would eventually be known as “Silicon Valley,” a community that was conceived of and parented by tech companies and Stanford. Palo Alto itself was a rather quiet community about 30 miles south of San Francisco, essentially continuous with the other towns strung down the peninsula. Josh and Esther warmly embraced the Californian lifestyle…

Stanford’s medical school was long on talent but short on space. Research conditions were cramped and people were frustrated. When Lederberg arrived in February 1959, his laboratory was in a somewhat dated biophysics building and comprised two large rooms stuffed with workbenches that were covered with agar plates, pipettes, esoteric tubing, autoclaves, handheld counters, and other paraphernalia. Esther Lederberg, and other researchers and assistants were crowded in there with him. Fortunately, Lederberg had a flair for not only envisioning new fields of study but also raising funds to support them.

Lederberg’s first five years at Stanford were intense as the young Nobel laureate was, as he put it, “transformed from a private person to a semi-public institution.” He was sought after for guest lectures at universities and international conferences, and he was on hiring committees for the new medical faculty, building up his small genetics department, and starting a new program of molecular genetics in his laboratory. He advised his young faculty on research directions, helped establish collaborations for them, and worked closely with the NASA laboratory to design instruments for detecting life on Mars. He suggested to engineers at NASA’s Jet Propulsion Laboratory that rocket ships could be fueled by “crystalline plasma.” He also advised on boards of tech companies and he fired off ideas on computer applications for science…

In the mid-1960s, Lederberg expanded his research interests far outside genetics. He introduced a time-share computer system for biomedical research — unheard of at the time in any medical faculty — and he developed an artificial intelligence system, one of the most successful ever applied to science. All of this occurred in a crucible unique to Stanford…

During the 1960s, Lederberg turned to address the scientific community and the public on the sociopolitical and ethical issues that would soon arise from biological engineering and molecular biology. The lack of forethought about biological engineering started to be clear to him in November 1962 when he participated in a four-day conference in London on “The Biological Future of Man.” That meeting had a profound impact on him, leading him to question not only what it meant to be a scientist, but also what it meant to be human…

Lederberg had been transformed by the London Symposium, “The Biological Future of Man,” in 1962. It broke him out of his solitude, his singular focus on developing personal knowledge, as he came to appreciate that knowledge itself was social and that communication was the object. “Science is a social phenomenon, rather than one of private insight,” he wrote to his friend Jack Edman: “… Surely the common ground of all philosophy is verbal expression, and I am surprised (not to be aware) more has not been made of this as an alternative to eclecticism… What shall I call it — cultural idealism: that reality is not a private idea but the idea of my cultural tradition, from which I learn all the means of knowledge. Put another way, reality is the rule of communication within a culture…” …

Senators and Congressmen, heads of federal funding agencies, and heads of private philanthropies read Lederberg’s columns in The Washington Post as he addressed many of the central issues of the day — from the potential hazards of untested chemicals in the environment to the promise of biological engineering and the sociopolitical and ethical issues that it engendered. Lederberg hoped to affect government policy, and in that regard perhaps nothing he wrote about was more important than when, in 1966, he called for a treaty to end the development of biological weapons…

No development in genetics offered more biomedical promise, in Lederberg’s view, than cutting desired bits of DNA from one species and splicing them into the genome of another. Those techniques would make it possible to use bacteria to make insulin, human growth hormones, vaccines, and other products for treating and preventing disease. Stanford’s medical school was where recombinant DNA techniques were first developed — most prominently in the biochemistry department. Techniques used to harness the enzymes that break and splice DNA were at the basis of this, and knowledge of nucleic acid biochemistry in Arthur Kornberg’s department was unparalleled…

A great public furor over recombinant DNA research broke out in the 1970s. While Lederberg saw its great promise for the study of cancer and pathogenic viruses, and for such medical products as vaccines and antibiotics, others pointed to environmental risk, public safety, and the ethics of “tampering with life” just for the curiosity of scientists. For the first time, some declared, the “species-barrier” that prevents genetic crosses between unrelated organisms had been broken. There was a range of reactions to this: some called for government guidelines restricting certain kinds of experiments, others wanted all gene-splicing experiments stopped, and still others were concerned about the partnership between university and industry that biotechnology seemed to entail…

Lederberg was getting restless by the late 1970s and decided to leave Stanford and move back to New York City to become President of the Rockefeller University. In some ways, he was coming full circle. The Rockefeller Institute, as it was then called, was where Avery and colleagues had produced evidence in 1944 that DNA might be the basis of the gene. That work had sent Lederberg down the path to bacterial genetics and earned him a Nobel Prize. Since then, as we have seen, that path branched off in many directions…

Lederberg often found being the fifth president of the Rockefeller University rather trying. It was hardly the pocket-sized department that he had headed at Stanford. With 60 laboratory heads and some 200 scientists, it was on a wholly different scale. But the challenge was not just in managing the scientists. He was hired at a time when the institution was in the midst of an identity crisis and under severe financial stress…

In 1986, when Lederberg suggested to his good friend, David Hamburg, then president of the Carnegie Corporation of New York, that he should establish a study commission on scientific advice to the government, Hamburg was receptive. Andrew Carnegie had established the foundation as a philanthropic fund in 1911 to support education programs in the United States, and later the world. The Carnegie Commission on “Science Technology and Government” began in 1988 as a five-year study aimed at assessing how different government departments might make use of science, and how scientists themselves could be more effective as advisory experts on science and technology issues. The study was highly influential; many of its recommendations have had a lasting effect. “I don’t think I would have done it if Josh did not want it so much,” Hamburg recalled…

The biological weapons and toxins treaty of 1972 relied on the good faith and commitment of the parties who signed it. But it also suggested mutual consultation among experts to help ensure compliance. Lederberg took to that forum over the next two decades consulting with Soviet scientists and with the US government. His first mission though, was in preventing further biowarfare development in the United States…

Greek mythology tells the story of the unrequited love of a heartbroken demi-god who wanted to punish the princess Cassandra for rejecting him. He bestowed on her the gift of prophecy and then he cursed her never to be believed. Lederberg sounded the alarm about coming plagues beginning in the 1960s with the then newly reported Marburg virus and Lassa Fever. He connected those outbreaks with his own fear that pathogens might be developed as biowarfare agents. Epidemics and biowarfare were joined at the hip — whether accidental or deliberate, they were threats to the nation, and the world, and required research and public policy to prevent…

Lederberg stepped down as president of the Rockefeller on July 1, 1990. It might well have been a relief to him, but he certainly had not intended to resign that year. He was 65 years old and would have continued on, but after 12 years, Rockefeller faculty wanted a change. In particular, the university needed a president who would be more actively engaged in fundraising. Hiring new faculty and making changes meant dipping into endowment funds, and the university was running a deficit…

Lederberg had the look of a distinguished polymath as he turned eighty in 2005. Slightly dishevelled, he spoke softly with his usual great precision and deliberation. “You sense not just intellectual power but moral force,” a journalist commented. “There is something prophetic about him.” But he was not in good health. He had spinal stenosis, a narrowing of spaces in the spine that put pressure on the nerves. His pain required medication that rendered him tired and often unable to focus…

The following sections are included:

• Endnotes
• Index