Emperor of Enzymes

The following sections are included:

• Dedication
• Foreword
• Preface
• Acknowledgments
• Contents

The story of Arthur Kornberg's family is a saga that was repeated by a multitude of Jewish refugees around the turn of the 19th century. Kornberg's paternal grandfather David Lieb Kornberg was born and raised in Russia, where he died in 1918, the year that witnessed the end of World War I. Kornberg's paternal family name was originally Queller (sometimes spelled Kweller), a name that derives from Cuéllar, of Spanish Sephardic origin, but it was abandoned by his grandfather to avoid conscription to the Russian army. “The army draft was a fate no orthodox Jew could contemplate; to escape it he had taken the name of one Kornberg who had already done his military service,” Arthur Kornberg explained in later years. Arthur's paternal grandmother Bella, who bore the maiden name Krell, was born in Denmark. David Lieb and Bella were cousins. Bella's death preceded that of her husband, an event that prompted him to marry Bella's sister, ostensibly to provide for her — not an uncommon custom among Jewish families of that era. No children issued from this marriage. David Lieb lost his second wife to illness as well. His third wife bore him three children.

The NIH traces its roots to 1887, when a one-room laboratory was created within the Marine Hospital Service (MHS), predecessor agency to the US Public Health Service (PHS). The MHS had been established in 1798 to provide for the medical care of merchant seamen. A clerk in the Treasury Department collected 20 cents per month from the wages of each seaman to cover costs at a series of contract hospitals. In the 1880s the MHS had been charged by Congress with examining passengers on arriving ships for clinical signs of infectious diseases in order to prevent epidemics, especially of cholera and yellow fever. Some years later the MHS authorized Joseph J. Kinyoun, a young physician trained in modern bacteriological methods, to set up a one-room laboratory in the Marine Hospital at Stapleton, Staten Island, New York. Kinyoun referred to this facility as a “laboratory of hygiene.” In due course the Hygienic Laboratory, as it came to be called, was moved to Washington, D.C., and was eventually recognized in law when Congress authorized funds for construction of a new building in which the laboratory could investigate infectious and contagious diseases as well as matters pertaining to the public health. In 1930 the name of the Hygienic Laboratory was changed to National Institute (singular) of Health (NIH). Over the years the term “institute” became pluralized as the NIH grew to become a physically massive and leading bastion of biomedical research.

In 1947 Kornberg joined another prestigious laboratory for six months of further postdoctoral training, one operated by the husband and wife team of Carl and Gerty Cori (nee Radnitz) in the Department of Pharmacology at Washington University in St. Louis, an institution to which he was destined to return in a considerably more senior capacity not too many years hence.

In 1952 Kornberg was comfortably ensconced at the NIH. His research was progressing to his satisfaction and his name was becoming a household one in biochemical circles. He had no thoughts of relocating anywhere. But he was becoming aggravated that in his capacity as a section chief he was required to periodically interact with senior NIH administrators — who he referred to as “less-than-inspiring.” Additionally, the Institute was then building a Clinical Center dedicated to research on patients with specific diseases of interest, and Kornberg harbored concerns that basic biomedical investigation, then an overarching feature of life at the NIH, would undergo a transformation to more clinically oriented agendas. In terms of his stability at that institution it might be said in retrospect that Kornberg was then ripe for the plucking. Nonetheless, having never held a faculty position at an academic institution he was more than a little surprised to be invited by Carl Cori and Oliver Lowry at the Washington University School of Medicine in St. Louis to consider assuming the recently vacated chairmanship of the Department of Microbiology (formerly the Department of Bacteriology and Immunology).

As the middle of the 20th century approached, no one had the faintest notion of how cells make DNA or RNA. Nor was the biosynthesis of the nucleotide building blocks of these macromolecules even established. “I freely admit that when the Watson–Crick paper came out I was not electrified by it, as I should have been,” Kornberg stated.

While grappling with the enzymology of RNA synthesis, Kornberg was also pursuing the biosynthesis of DNA. He searched for evidence of DNA synthesis in vitro by measuring the incorporation of radiolabeled thymidine into an acid-insoluble product, a property expected of nucleic acids. He initially obtained radiolabeled thymidine as a gift from Morris Friedkin in the Department of Pharmacology at Washington University, who had a solution enriched with the compound left over from one of his own experiments. Kornberg found the results dubious. After one hour of incubation very little of the radioactive thymidine was converted to an acid-insoluble state. It took almost a year before Kornberg repeated this experiment. This time he used a thymidine solution with three times the amount of radioactivity present in his first trial. Once again only a tiny amount of the nucleoside was incorporated into acid-precipitable material. But he was encouraged to observe that the radioactive product was susceptible to digestion by pancreatic deoxyribonuclease (DNase), an enzyme purified and crystallized by Moses Kunitz at the Rockefeller University in 1950, which specifically degrades DNA. Kornberg was convinced that he had discovered a new enzyme, which he named DNA polymerase, though he readily admitted that without the encouragement of the diagnostic result that DNase yielded he wondered whether he would have had the will to “pursue such a feeble light.”

Prior to the mid-1950s the Stanford Medical School was geographically split. The basic sciences, including biochemistry, which was taught by Herbert Loring and Murray Luck in the Department of Chemistry, took place at the Stanford campus in Palo Alto. However, clinical training was provided at hospitals in San Francisco, a good 30 miles north. The decision by the university to consolidate its medical school entirely at the Stanford campus consumed protracted and often-contentious discussion. In his book Biotech — The Countercultural Origins Of An Industry, Eric Vettel summarized the combative atmosphere that preceded the move. “A meeting with the University Board of Trustees in May 1953, just two months after Watson's and Crick's famous discovery, a wake-up call to many academic institutions aspiring to state-of-the-art basic biomedical research, afforded Stanford Provost Fred Terman the opportunity to restructure and reorganize the biological sciences,” Vettel wrote He was strongly supported by President Wallace Sterling, who spoke forcefully on the topic. “We have a medical school problem,” Sterling told the trustees. “Medical education, which is now in a state of flux, is inextricably tied to the basic sciences. ------------------ The key is the relationship of medical education --- to other scientific fields.” Then Sterling offered an unexpected and startling solution: “bring the Medical School into the closest possible physical and intellectual relationship to the whole University.”.

Kornberg thought long and hard about how best to organize his Stanford department, as well as settling it into the life of the medical school and the university. “His plan was to create the ideal work place, one in which individual research groups would cooperate with one other and nothing would interfere with the progress of their research endeavors,” Buzz Baldwin wrote in a tribute to Kornberg shortly after his death in 2007.

Following the many invited seminars and lectures that Arthur Kornberg presented during the 10 years between 1957 and 1967, he was frequently asked the vexing question: “Why have you been unable to replicate the genetic activity of the DNA product synthesized in vitro?” “Of course, we had tried many times to replicate the DNAs from Pneumococcus, Hemophilus, and Bacillus subtilis, each with readily measured transforming activity,” he wrote. “These DNAs performed adequately as template-primers for net synthesis of DNA, but there was always a net loss rather than an increase of biological activity.”.

As mentioned earlier, Arthur and Sylvy Kornberg raised three sons, Roger David, Thomas (Tom) Bill, and Kenneth (Ken) Andrew, born in 1947, 1948 and 1950, respectively — years when Arthur was at the NIH in Bethesda, Maryland. At the time of this writing all three enjoy successful professional careers, Roger and Tom as academic scientists at Stanford University and the University of California at San Francisco respectively, and Ken as an architect with special expertise in designing science laboratories.

“Those familiar with my research career are aware of my intense concentration on a single subject — the enzymatic synthesis of DNA — and the blinders I have worn to maintain this focus,” Kornberg wrote in his autobiography For the Love of Enzymes: The Odyssey of a Biochemist. “Nearly forgotten now by us all are the eight years, in the midst of the DNA work (1962–1970), when half of my research effort was devoted to an arcane subject, the development and germination of spores.”

The biochemical studies on DNA replication ongoing in Kornberg's Stanford laboratory were complemented by work in other laboratories around the world, a number of which incorporated the genetics of replication, studies that revealed the existence of multiple genes, and by inference the requirement of multiple proteins to successfully consummate the faithful copying of DNA in living organisms. Steady progress in the field notwithstanding, crucial questions remained to be answered, many of which Kornberg thoughtfully pondered. “How is a DNA chain started?” he asked.

In the mid-1950s, while still at Washington University, Kornberg and his wife Sylvy became interested in a compound called polyphosphate (PolyP): linear polymers containing a few to several hundred residues of orthophosphate linked by energy-rich phosphoanhydride bonds. PolyP is ubiquitous in Nature, but its function(s) is (are) poorly understood. When asked by Sally Smith Hughes what prompted him go off in the direction of polyphosphate, Kornberg related that he once gave a seminar at the University of Wisconsin, and as is standard during such visits, he was shuttled around to various scientists who wished to meet with him.

Arthur Kornberg was an articulate and prodigious writer, an activity he clearly enjoyed, as evidenced by his prolific and enduring output of written material. The 463 publications listed in his curriculum vitae include multiple essays, editorials and commentaries on various aspects of basic biomedical research (see Appendix). He prepared thoroughly for invited lectures and talks, frequently making comprehensive written drafts in anticipation, and typically completed such writing well ahead of time. His son Roger recalls that when his father once gave a named lecture in the United Kingdom that required a manuscript scheduled for publication many months later Kornberg delivered the completed paper at the time of the lecture. The lecture organizers were so astounded at such an early delivery that they asked him to take it back, pleading that they were totally unable to deal with it at the time of the lecture for fear that they may lose track of it!

Kornberg frequently deployed his pen to focus attention on government funding of biomedical research. In an editorial entitled “The Support of Science” published in the journal SCIENCE in June 1973, he drew attention to the financial attrition scientists were then facing.

Historically, the association of scientists with the private sector was largely, if not exclusively, limited to physicists and chemists. Only a small minority of the graduates of chemistry departments traditionally joined the academic sector. “Chemistry departments were tightly linked with industry,” Kornberg told interviewer Sally Hughes. But until the decade of the '70s it was tacitly accepted that it was immoral for scientists in the biological research community to receive monetary reward for consultative activities. “In biology it was utterly unknown,” Kornberg stated.

Arthur Kornberg was at the lab bench probing the secrets of polyphosphate until very shortly before his death on October 26, 2007. “One Friday afternoon his secretary at Stanford called me and told me that he was not doing too well,” his wife Carolyn related.

The following sections are included:

• Appendices
• Index