"Sally Smith Hughes skillfully describes the improbable creation, difficult adolescence, immense prosperity, and eventual foundering of Genentech, the first biotech behemoth. It’s a great tale, with a cast of fabulous characters and surprising episodes, ranging from Palo Alto to Wall Street. This is an outstanding book that should appeal to Nobel laureates as well as hedge-fund barons and ordinary citizens.”

Genentech

The University of Chicago Press

Contents

Chapter One

I looked at the first gels [in the first recombinant DNA cloning experiment], and I can remember tears coming into my eyes, it was so nice. I mean, there it was. You could visualize your results in physical terms, and after that we knew we could do a lot of things. Herbert W. Boyer, March 28, 1994

Modern biotechnology originated in 1973 with the invention of recombinant DNA technology, a now-universal form of genetic engineering. It entails recombining (joining) pieces of DNA in a test tube, cloning (creating identical copies of DNA) in a bacterium or other organism, and expressing the DNA code as a protein or RNA molecule. It soon vastly extended the power and scope of molecular biology, penetrated several industrial sectors, and became a cornerstone of a new industry of biotechnology. Yet technological power and potential cannot alone explain its first commercial application—at the biotechnology company Genentech in the mid-1970s. Stanley Cohen and Herbert Boyer, the two inventors, had designed the technique for basic-science research. But they immediately foresaw its practical applications in making plentiful quantities of insulin, growth hormone, and other useful substances in bacteria. Despite their common starting point, Cohen and Boyer chose different avenues for industrializing recombinant DNA technology. Why they did so was a matter of personality and professional commitments. It was also a matter of the national environment in the U.S. of the 1970s—a pivotal decade of raging debate in science politics, major dilemmas and decisions in constitutional and patent law, and cultural, attitudinal, and personal challenges as commercial interests first entered molecular biology full force.

TWO SCIENTISTS ON CONVERGING PATHS

Herbert Wayne Boyer was born in 1936 into a blue-collar family and grew up in the little town of Derry, thirty miles from Pittsburgh in the coalmining country of western Pennsylvania. His father had left school in eighth grade and eventually found work as a railroad brakeman and conductor. His mother married straight out of high school and stayed home to look after Herb and a younger sister. Herb earned pocket money by mowing lawns, delivering newspapers, and doing other odd jobs of a middle-American boyhood. He hunted and fished with his father and developed an abiding love of the outdoors. All four Boyers played at least one musical instrument and regularly got together with family and friends to play country-western music—bright spots in an otherwise workaday world. Herb's first years at Derry Borough High School were a steady round of football, basketball, baseball, and girls—anything but academic achievement. He was on "a rather perilous course of delinquency," 2 he later admitted. It took a no-nonsense football coach and teacher to jolt Herb out of his apathy. "Pat Bucci straightened me out," he subsequently observed. He began belatedly to focus on schoolwork. Coming into his own, he was elected junior- and senior-class president and voted most athletic. But the limited vistas of a small railroad town felt more and more confining. One way or another, he had to get out. Herb resolved to go on to college, the first in his family to do so. He was off to troll wider horizons but destined never to lose the down-to-earth practicality and lack of pretension of his blue-collar upbringing.

Stanley Norman Cohen is also the first child and only son of parents whose formal education ended with high school. His father was a small businessman who tried his hand, never very successfully, at several trades in and around their home in Perth Amboy, New Jersey, a town just southwest of New York City. Stan's mother worked for a time as a secretary to make ends meet. Stan was born in 1935 and raised as an only child until the birth of a sister when Stan was almost ten. Tight finances, gentle discipline, and parental ambition for their children to rise in the world largely defined home life. While Boyer needed Coach Bucci's intervention to provoke his attention to schoolwork, learning came naturally and at an early age for Cohen. No adult had to build discipline in young Stan. "I suppose," he recalled, "that overall I wasn't much of a wayward kid, so there really wasn't a lot of need for discipline." He and his father, a frustrated inventor, spent off-hours in the basement doing small wiring and mechanical projects. Cohen credits his father with sparking his interest in how things work—sparking his interest in science. From the start he was motivated to achieve, and achieve he consistently did. In high school he was editor of the school paper and associate editor of the yearbook. By then his scientific interests centered on biology, which to Stan meant becoming a physician. He now had a goal that would move him beyond the narrow scope of his upbringing. Yet he would remain stamped with the work ethic, professional ambition, and respect for knowledge of his Jewish heritage.

Boyer and Cohen, with only slightly more than a year between them, came of age in the early 1950s. Both were financially strapped; both could expect no financial assistance from their families; both chose colleges close to home. In 1954 Boyer entered Saint Vincent College, a liberal-arts institution run by Benedictine monks in Latrobe, Pennsylvania, a few easy miles from Derry. He lived at home to save money and hitchhiked or rode the bus to and from classes. His father, a railroad man, refused to learn to drive, let alone to buy a family car. Boyer majored in biology and chemistry, intending to go on to medical school. A chance class assignment suggested another direction. More than five decades later, Boyer recalled the shift with the clarity of a formative moment:

We had a brand-new, shiny [cell physiology] textbook with a blue and white cover. Each of us was assigned a chapter, and we had to give a seminar on it. Which one did I get? "The Structure of DNA." This was 1957, and the buzz of DNA was just getting into the textbooks.... I was really taken with the Watson-Crick structure of DNA and this started my fascination with the heuristic value of the structure.

A sign of his new infatuation was Boyer's Siamese cats, Watson and Crick. In 1958 Saint Vincent awarded Boyer a bachelor's degree in biology and chemistry.

Boyer applied and failed to enter medical school, a D in metaphysics being his nemesis. He settled on graduate school at the University of Pittsburgh, partly to improve his grades and reapply to medical school, partly because "a small-town boy doesn't stray too far from home." He craved intellectual stimulus and found it in the heady research of a bacterial genetics laboratory at a watershed moment in molecular biology. Watson and Crick's discovery of 1953 had launched an avalanche of work on major questions—prime among them, the nature of the genetic code and the mechanism of protein synthesis. Much of this research transpired in bacteria, employed by experimentalists for their relative simplicity as compared to the animal kingdom. Boyer thrived on the lab's scientific ferment and freeform discussion on genetic exchange and recombination in bacteria. "That [lab]," Boyer recalled, "was my [scientific] awakening."

In 1959, at the end of his first year of graduate school, Boyer married his high school sweetheart, Marigrace Hensler, a biologist in her own right. She gamely supported the couple, as Boyer tackled a nearintractable experiment on deciphering the genetic code. Breaking the code was the foremost problem in molecular biology of the day, one that only a supremely ambitious—or naive—graduate student would agree to take on. Boyer did and plugged away, even after two biochemists broke the code in 1961. "Boyer," a future colleague commented, "consistently tried big things without knowing whether they could or should work." He managed to squeeze out enough data to complete a dissertation. His attraction to challenging problems would become a mark of his professional career. Boyer was setting an enduring pattern. Below the casual surface lay ambition and tenacity. In 1963 Boyer earned a doctoral degree in bacteriology.

Cohen chose Rutgers University, a few short miles from Perth Amboy. Rutgers offered the most scholarship support and was close to his ailing father. Studious as ever, Cohen worked hard but carried to extremes his resolve to make a life beyond academics. He joined the university debating team, took up the guitar, and tried his hand at writing pop songs, one of which reached the hit parade. This flurry of extracurricular activities, predictive in its intensity, failed to dent his academic performance. In 1956 he graduated magna cum laude from Rutgers. That fall Cohen entered medical school at the University of Pennsylvania, a major draw being the substantial scholarship funds it provided. His first taste of basic research in the second year led to a summer research position in London and to the publication of his first paper. He took time off that summer to wander the cafés of Europe, supporting himself by singing and strumming the banjo. "It was a wonderful time," he recalled, remembering the freedom and lack of responsibility. Life from then on would never again be as carefree, but banjo and song would remain outlets for life. In 1960 Cohen graduated from Penn with a degree in medicine. Within a whirlwind five-year period, swinging from the East Coast to the South, Cohen completed an internship, a two-year research position at the National Institutes of Health (NIH), and a residency in medicine. In 1961 he married Joanna Wolter, and they eventually had two children.

Boyer's career took a less peripatetic course. He went straight from Pittsburgh to Yale as a postdoctoral fellow in microbiology. There he joined a lab focused on genetic exchange and recombination in bacteria. He became fascinated with the restriction enzymes of bacteria—enzymes that cut up and destroy foreign DNA entering the bacterial cell. The word just emerging in the 1960s was that certain types of restriction enzymes sever DNA at unique sequences in the molecule. Perhaps, Boyer and others recognized, one could use these strange enzymes to clip DNA into well-defined fragments and map its structure. He suspected early on that restriction enzymes were going to be "very helpful enzymes" for the precision cutting, recombination, and characterization of DNA. The suspicion was prophetic: his career-long passion would become restriction enzyme research and genetic manipulation. Boyer now lived and breathed his science. After a night on the town, he would return to the lab or rise in the dark to observe an experiment. But the folks at home were stymied. "What are you doing?" his father would ask. "Restriction endonuclease modification," he would glibly answer, using the technical term for his research area. He would then pause for his father's inevitable retort, "Well, what good is it? What are you going to do with that?" Boyer would respond, "I don't know—cure the common cold." His answer was dismissive, but his father's question prompted him to ponder the practical utility of his research.

Cohen meanwhile had begun a postdoctoral research fellowship (1965–67) in molecular biology at Albert Einstein College of Medicine in New York. It was here he stopped wavering between a career in medicine or science. He decided to pursue both, apparently expecting the rewards of a dual career to outbalance its tensions and frantic pace. He took up research on plasmids, tiny rings of DNA in the cytoplasm of bacterial cells that reproduce outside the main chromosome. Plasmids typically carry antibiotic resistance genes that can pass from one bacterium to another, spreading the resistance problem. The study of plasmids was at the time a quiet backwater and to Cohen consequently appealing. Scientists interested in genetic exchange and gene regulation mainly studied viruses, which had been a central focus of molecular studies from the 1930s on. Cohen reasoned that his heavy clinical responsibilities would make successful competition with "hotshot" molecular biology labs difficult if not impossible. Plasmid research seemed a perfect fit: he knew the necessary molecular and biochemical techniques, and the growing medical problem of antibiotic resistance was an appropriate topic for a physician. He was correct in every regard except for expecting the field to remain tranquil. It was about to explode, and Cohen would find himself at its epicenter.

By 1968 Cohen was intent on finding a faculty position. One of his mentors had collegial associations with several members of the biochemistry department at Stanford University. The connections led to a job offer, but not in biochemistry. Some years earlier, the clinical departments at Stanford Hospital in San Francisco had moved south to join the preclinical departments on Stanford's Palo Alto campus—a reorganization aimed at bringing basic science and clinical medicine into geographic and intellectual proximity. Recognizing Cohen as one of a new breed of physician-scientists the school sought to attract, the Department of Medicine offered Cohen an assistant professorship in its Division of Hematology. Cohen, drawn by the California climate and lifestyle, accepted and in 1968 moved with his wife to the sun-swept campus in Palo Alto.

He was disheartened to find that no one in the department shared his fascination with molecular genetics. He turned for advice to Arthur Kornberg, the powerful chairman of Stanford's biochemistry department. By virtue of his Nobel Prize, academic position, and forceful personality, Kornberg was a figure to reckon with. Not one to mince words, he told Cohen that plasmid research was an uninteresting line of investigation. The irony of the remark would soon become apparent. "So this wasn't a very comforting introduction to Stanford," Cohen recalled. His understatement skated over what must have been an unsettling blow: he had come to Stanford considering that shared scientific interests and collegial ties might lead to a joint appointment in the Department of Biochemistry. Instead, Kornberg made it clear that Cohen's association with the department was at best to be informal. Kornberg almost never granted joint appointments and also believed that only a rare individual could optimally perform both clinical medicine and basic research. Despite the tepid welcome and even after his own lab was operating, Cohen, according to biochemist Paul Berg, "hung around in [the Department of] Biochemistry most of the time."

Berg exaggerated, but Cohen indeed thrived on the department's stimulating intellectual exchange and had access to its electron microscope and other equipment lacking in his home department. He regularly attended biochemistry seminars and benefited from the chance "to bounce ideas off people in that department." He particularly profited from discussing ongoing departmental research on DNA ligation (joining) and DNA uptake by animal cells. In turn, he shared with biochemistry colleagues his work on plasmid isolation and characterization. But the research Cohen published in the early 1970s was not done in collaboration with Stanford biochemistry faculty. As he stated forcefully in 2010: "Notwithstanding Kornberg's notion that all important scientific knowledge at Stanford originated in the Department of Biochemistry, the work on DNA replication in that department had absolutely zero impact on my research. Similarly, the work on biochemical methods of dAT joining"—a biochemical method for joining DNA fragments—"by Berg and others did not impact my work."

(Continues...)

Excerpted from Genentechby SALLY SMITH HUGHES Copyright © 2011 by The University of Chicago. Excerpted by permission of The University of Chicago Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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