Professor Arthur Kornberg

Nobel prize-winning biochemist whose research into enzymes helped unravel the mystery of DNA

Saturday 03 November 2007 01:00

Arthur Kornberg, biochemist: born Brooklyn, New York 3 March 1918; Head, Enzyme and Metabolism Section, National Institutes of Health, Bethesda 1942-52; Professor of Microbiology, Washington University 1953-59; Professor of Biochemistry, Stanford University 1959-88 (Emeritus), Head of Department 1959-69; Nobel Prize in Physiology or Medicine (jointly) 1959; married 1943 Sylvy R. Levy (died 1986; three sons); 1988 Charlene W. Levering (died 1995); 1998 Carolyn Frey Dixon; died Stanford, California 26 October 2007.

Arthur Kornberg was among the leading biochemists of the 20th century. His most important scientific contribution was the discovery of an enzyme, DNA polymerase, which synthesises DNA and in so doing copies the DNA template. For this he shared the Nobel Prize for Physiology or Medicine in 1959 with Severo Ochoa who had discovered an enzyme which makes RNA. He then went on to use this enzyme to help establish the structure of DNA proposed by Watson and Crick and to understand how the bacterial chromosome is replicated.

Kornberg was born in Brooklyn in 1918 and gained his first degree in chemistry and biology at the City College of New York. He was trained in medicine, being awarded an MD from Rochester University in 1941 and, after a brief spell as a doctor on board ship in the US Navy and at the National Institutes of Health (NIH), he spent a formative year in 1946 learning how to purify enzymes with Severo Ochoa at Columbia University. He returned to the NIH as the chief of their Enzyme and Metabolism Section for a decade before moving to Washington University in St Louis where he was the chairman of the Biochemistry department. It was here that he discovered the DNA polymerase.

In 1959 he moved to Palo Alto to assist in establishing the new campus for Stanford University and, in particular, its Biochemistry department. He was the chairman of this department for 10 years, but continued with his research until his death.

The 1950s were heroic days for biochemistry when many new reactions and biochemical processes were discovered. Prior to 1956, Kornberg made wide use, as did many others, of radioactive isotopes to trace how complex molecules are synthesised in cell extracts. In his case, he focused on nucleotides and deoxynucleotides believing these to be the likely precursors of the macromolecules RNA and DNA.

Armed with these reagents, he discovered in 1956 the bacterial DNA polymerase, or "Kornberg enzyme" as it came to be known, which we now know is one of a family of such enzymes. This was a watershed for understanding the biosynthesis of polymeric molecules in general and nucleic acids in particular.

Over the succeeding years he and his colleagues, including his first wife Sylvy, purified his enzyme to homogeneity and studied its functions and used it as a tool for DNA research. Most importantly, he found that it requires a template DNA, which it copies faithfully. In addition, all four of the precursor nucleoside deoxytriphosphates (dATP, dTTP, dCTP and dGTP) have to be present to copy the DNA, a requirement which makes sense given the chemical nature of the linear strand of DNA being copied. It may be noted that these small precursors were not available commercially as they are now; each had to be synthesised by Kornberg.

DNA polymerase enabled new types of DNA to be made and their physical properties understood. Thus, early on, Kornberg discovered that if DNA polymerase is left to idle without a template and with only the two precursors, dATP and dTTP, it starts doodling and somehow makes a new DNA composed solely of alternating As and Ts. In 1961 he developed the "nearest neighbour" method for determining the average neighbour relationship of bases along the DNA chains. From this, he was able to prove that the two strands of DNA in the double helix run in opposite directions: one up, the other down.

This was an extraordinary piece of chemical evidence, coming from an entirely unexpected quarter: it supported the double helical structure for DNA which had been based largely on X-ray studies and model building. Much later, with the advent of the cloning of genes, DNA polymerase became one of the most useful tools in the cloner's tool-kit.

After the discovery of DNA polymerase, Kornberg and his colleagues turned their attention to the very complex matter of how bacterial chromosomes are replicated. Not only do the two strands of the double helix need to be copied, but the resulting two helices have to be separated from each other, a problem presenting great topological difficulties. There exists in the cell an extraordinary set of machinery for replicating, unwinding, assembling and proof-reading the genetic copies. Kornberg's Stanford group were pioneering students of this machinery and their work has led to our present understanding of this process.

But he also branched out to study sporulation. His mother had earlier succumbed to gangrene caused by a spore infection, leading to his interest in spores – how they form, how they can be dormant for a long time and yet emerge when growth conditions become more favourable. Later on the main focus of his research was on the role of the phosphate polymer, polyphosphate, which is found in bacteria, plants and animals.

The new department he established at Stanford in 1959 soon became one of the leading departments of biochemistry in the United States: among his colleagues were Paul Berg (who helped develop modern cloning methods), Bob Lehman, Dale Kaiser, Buzz Baldwin and David Hogness, all stars in their respective fields. The success of this department owed much to Kornberg's personality and the way in which he made it like an extended family. Each summer he and Sylvy would entertain the department for an afternoon party with swimming, games and a barbeque at their wonderful house. This was sited on Golden Oak Drive atop a small hill above Palo Alto with a panoramic view across the bay and over to San Francisco. The department itself was also unusual in the manner in which space, reagents and equipment were shared – quite different from the norm in which individual group leaders would jealously guard their areas and the equipment they had purchased with their own grants.

In the 1960s and beyond, Stanford became the world centre for nucleic acid research and there were many fruitful collaborations between the groups. In addition, visitors came to learn and use the in-house technology and take advantage of the unique collection of enzymes. For example, Gobind Khorana was a frequent guest in the middle 1960s, learning how to use these reagents to build synthetic DNA polymers with repeating sequences and which he then used at his home base in Madison, Wisconsin, to determine their coding properties: this led to the full elucidation of the genetic code.

The success of his department owed much to Kornberg's personal qualities: tough, but gentle and gracious. His colleagues greatly respected his unparalleled knowledge of much of biochemistry, and a perspective which came from having participated in its history. When a visiting post-doc left an untidy heap of samples in his lab late one evening, Kornberg was right there to meet him when he arrived next morning. Walking him down the corridor he said, "Mark, if you do that again, you won't be so welcome here". With this mild rebuke from the top, the lesson was learned: it ensured that the department was tidy, efficient and ran smoothly, and this earned for Kornberg everyone's respect. It was said that he expected each of the graduate students would one day chair a biochemistry department elsewhere in the United States. This is more or less what happened, providing his department with a major legacy in shaping biochemistry departments across the country. He wrote several books on DNA and its replication: these inspired a generation of researchers and students to appreciate the beauty of DNA and the complicated processes which must occur for life to multiply.

Kornberg's strong conviction was that only through a deep understanding of biochemistry could medical treatment become rational: his passion was understanding enzymes. He seemed to wish to know the details of their personalities and to believe that only through them would one understand how each worked; this is reflected in his autobiographical memoir written in 1989, For the Love of Enzymes: the odyssey of a biochemist.

He was a person of great persuasive powers and kindness and a whimsical sense of humour. One morning, touring the labs he discovered one of his recently arrived graduate students fractionating some radioactive material on a column. The student had placed a heavy lead-based protective perspex screen between himself and the column and was additionally wearing protective gloves and a lead apron. Kornberg says "Gee, David, what have you got there?" and David replies "some labelled nucleotides". Kornberg, full of bonhomie, says "Gee, and how much do have there?" to which the reply was "20 microcuries". Kornberg responds "But David, that's what I have for breakfast each morning!"

Arthur Kornberg had three sons, two of whom have followed in his footsteps. Roger received the Nobel Prize for chemistry in 2006 for his work on the yeast RNA polymerase, and Tom discovered two new and crucial DNA polymerases. A third son, Ken, is an architect.

Mark S. Bretscher

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