For the love of enzymes...
A tribute to Arthur Kornberg (1918 - 2007)

Arthur Kornberg loved enzymes, which repaid his affection again and again by revealing the most intimate secrets of life. His passing on October 28th, 2007, at the age of 89 marks the end of a great era in biochemistry and molecular biology, in which Kornberg played a central colossal part. Not only was he a brilliant scientist himself, but he nourished and encouraged hundreds of others and built a Department of Biochemistry at Stanford University that was the envy of the world, and at the very heart of the recombinant DNA revolution.

Arthur Kornberg also possessed considerable literary gifts, and his autobiographical odyssey “For the love of Enzymes” (Harvard University Press, 1989) is a brilliant book that should be required reading for molecular biologists, for the insights it provides into doing science. It’s also a warm and graceful account of a life that started out poor in Brooklyn. Arthur was the son of Jewish immigrant parents, and he worked in the family store at age 9. He did well in school and went to CCNY as a science major, where he worked evenings, weekends and holidays as a clothing salesman for $14 a week, managing to save enough money to pay his way through medical school at the University of Rochester, where biochemistry was dull, but physiology and anatomy “awesome”. But despite doing very well, ethnic and religious prejudice prevented him from being offered the Fellowships in medicine he felt he deserved, and he ended up in the Navy as a ship’s doctor. Unhappy with arbitrary naval authority, it came as relief to Kornberg himself and probably his Captain as well when the Director of the NIH summoned him to Bethesda to work in the Department of Nutrition, partly thanks to a fine research project on jaundice that Kornberg published in 1942, but also helped by a personal recommendation from his classmate, Leon Heppel. But the science of nutrition had seen its best days, and as soon as the war ended, Kornberg persuaded his boss to let him go to work on enzymes for a year with Severo Ochoa at NYU, and then for 6 months with Carl and Gerty Cori at Washington University in St Louis, where Arthur and Silvy’s first son, Roger was born “in a dim, warm burrow next to the house furnace”. They were searching for the key to the oxidative regeneration of ATP from ADP. But the secret of ATP was not to be revealed – it was a “doomed quest” because the enzymes they were looking for were embedded in the mitochondrial membranes, insoluble and inaccessible to biochemists of the school of the great Otto Warburg. Moreover, rabbits were expensive, the summer was extremely hot — the temperature in the laboratory rose above 37˚— and the Kornbergs were not sorry to leave the Midwest.

Thus it was that Kornberg returned to the NIH with a project to study NAD pyrophosphorylase, an activity he had discovered in St Louis. This fateful choice was to lead within 10 years to DNA polymerase. But first, a careful survey of a suitable source of the enzyme led from livers and kidneys to potatoes, and then a search for the best variety of potato, which had eight times as much enzyme as the worst. This little episode is very typical of the man, and is one of my favorite passages in his book (pp 72-3), where it is followed by the famous declaration: “I have never met a dull enzyme” —from the humblest hydrolase to the most glamorous polymerase — “the feats of all enzymes are awesome” and “Without knowing and respecting enzymes, better still loving them, answers to the most basic questions of growth, development and disease will remain beyond reach”. Kornberg proceeded to work out where the P of NADP was located, to discover the importance of reactions that produce pyrophosphate during investigations of the biosynthesis of NAD, and establish the role of orotic acid in the biosynthesis of pyrimidines and the role of PRPP in the biosynthesis of the nucleotides. These studies of nucleotide synthesis were the crucial enabling steps for the study of DNA synthesis.

In 1953, Kornberg left the NIH and returned to Washington University in St Louis, as Chairman of the Medical Microbiology Department. By 1956, in a crowded little laboratory, the first signs of DNA synthesis were apparent, and armed with good starting material, which proved to be exponentially growing bacteria, and a reliable assay – the incorporation of labelled thymidine as TTP into acid-insoluble, DNAse-sensitive material, the excited team were able to purify DNA polymerase in a remarkably short space of time, and submitted two papers to the Journal of Biological Chemistry in October 1957. They immediately ran into trouble from the reviewers, who included the scathing Erwin Chargaff. Some objected to the name “DNA polymerase”, while Chargaff insisted that the authors demonstrated genetic activity on the part of their newly-synthesised material. A whiff of vitalism lingered around experts on the genetic material, it seems. Kornberg was a great believer in the idea that life can be explained by chemists. He was critical of Louis Pasteur, whose “exaggerated interest in biology eventually caused him to neglect his chemical roots and thus delayed the advent of modern biochemistry and the discovery that enzymes are the vital force of fermentation”. Anyway, by the time 10 reviewers had judged the papers, Kornberg was on the point of sending them elsewhere when John Edsall, about to assume the position of Editor in Chief, stepped in and insisted that they appear, which they duly did in May 1958. They mark the beginning of a new age, the age of molecular biology, although Arthur Kornberg would never agree to being anything but a card-carrying biochemist, and proud of it. They are modest (though firm) in their conclusions, too, and the following papers tried as far as possible with the limited, if ingenious, tests available at the time to demonstrate that the newly made DNA was a copy of the DNA that was added: it took a little time to get across the central importance of the primer and template requirements, and even longer to convince the critics that DNA polymerase was the real thing. I can well recall discussions a decade later in Cambridge, scoffing at the work of the Stanford group, and there was considerable schadenfreude when John Cairns isolated the strain of E. coli that lacked “The Kornberg enzyme”. It became clear that DNA polymerase I, the Nobel Prize-winning enzyme was not the real replicative polymerase, but amazingly it fell to Tom, Kornberg’s youngest son, who was at the time a cellist at the Julliard School of music in New York, to find the real thing in only a few months of working with Malcolm Gefter at Columbia University. Eventually, it turned out that the properties that Arthur Kornberg and his colleagues had so painstakingly elucidated for Pol I also held true for Pol III; there was nothing wrong with the basic principles. An equally astonishing discovery was made by Reiji Okazaki, a former student of Kornberg’s, who found that DNA in cells was made in short pieces! This began to explain how the replication fork moved forward even though DNA polymerase could only add nucleotides to the 3’ end of the growing DNA chain, so that one chain somehow had to be copied backwards. Eventually, the Stanford group managed to achieve the amazing feat of producing working copies of M13 phage DNA, and they themselves were astonished at how complicated were the details. Had they but known this at the outset, back in the mid-1950s, they might well have been deterred from even trying. At the age of 75, Kornberg more or less stopped working on DNA replication and turned his attention to polyphosphate synthesis, something he and his first wife Silvy had discovered and worked on in the early 1950s. He published more than 50 papers on this neglected topic, working on it right up to his death, and pointing out its importance for the survival of bacteria in the wild in a clutch of beautifully written reviews.

When Kornberg moved to Stanford, he took with him many very talented biochemists, and his move prompted several other gifted scientists to help set up the new medical school; Buzz (R.L.) Baldwin, Paul Berg, Mel Cohn, David Hogness, Dale Kaiser, and Bob Lehman provided the core faculty at the outset, and Joshua Lederberg and Charles Yanofsky started the Departments of Genetics and Biology. In the early 1970s, Lobban and Kaiser and Jackson, Symons and Berg were among the first to make chimeric DNA molecules, and it was not long before Stanley Cohen and Herb Boyer teamed up to make the first viable cloning vectors. The patents for recombinant DNA belong to Stanford University.

Arthur Kornberg was rightly proud of his many achievements, but especially proud of his family. Roger Kornberg followed closely in his father’s footsteps, and was awarded the 2006 Nobel Prize for Chemistry for his studies of  “the molecular basis of eukaryotic transcription, as well as being elected a Foreign Member of EMBO. Tom Kornberg is now a Drosophila developmental geneticist at UCSF, while his brother Ken runs an architectural firm that specializes in the design of laboratories.  The last time I met Arthur Kornberg was in 2005, at a celebration of the 100th anniversary of Severo Ochoa’s birth, presided over by the King and Queen of Spain. Arthur made a charming speech about Ochoa, who had introduced him to enzymes in the first place, but I was amused and warmed to overhear him boast of his three sons’ achievements to Juan Carlos I of Spain, as one dad to another. Arthur Kornberg was a giant in many ways, and I rather doubt if we will see his like again.

Tim Hunt, November 2007.

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