"It has been my conviction . . . that you have to know the actors in order to understand the plot. And the actors are the enzymes. They are the mini-chemists, the devices by which a biological phenomenon takes place . . . whether it is the legendary question of alcohol fermentation . . . or how a firefly comes to luminesce."
During a research career spanning more than sixty years, Arthur Kornberg made many outstanding contributions to molecular biology. He was the first to isolate DNA polymerase, the enzyme that assembles DNA from its components, and the first to synthesize DNA in a test tube, which earned him a Nobel Prize in 1959. He later became the first to replicate an infective virus DNA in vitro. He was the primary architect and first chairman of the Department of Biochemistry at the Stanford University School of Medicine, which under his guidance became a preeminent center for DNA research, including recombinant DNA research. Starting in the 1980s, Kornberg also played a key role in establishing productive ties between academic science and the biotechnology industry.
Kornberg was born in Brooklyn, New York on March 3, 1918, the youngest of Joseph and Lena Kornberg's three children. Emigrants from eastern Europe, the Kornbergs owned a small hardware and home furnishings store. Arthur was "an eager and able student" and was allowed to skip grades several times in primary school. He finished high school at age 15, and entered the City College of New York in 1933. Despite this precocity, Kornberg doesn't recall having any early passion for science, or interest in the natural world as a youngster. (He collected matchbook covers rather than butterflies.) He did well in his high school and college chemistry courses, and briefly considered an academic career in the field. During the Depression years, however, medical school seemed a more promising choice. Kornberg received his MD from the University of Rochester in 1941, expecting to become "an internist with academic connections." Following his internship, he began his World War II military service as a ship's doctor on a U.S. Coast Guard vessel in the Caribbean. Though he often quarreled with the ship's captain, Kornberg expected to remain on sea duty for the duration of the war.
Kornberg's career took an unexpected turn when his first medical article was published in 1942. In medical school, Kornberg had conducted a small research study into a disorder (later known as Gilbert syndrome) characterized by excessive bilirubin in the blood and a mild benign jaundice, because he himself had the condition. At the time of publication, senior military medical officers, along with National Institutes of Health (NIH) director Rolla Dyer, were desperately seeking out new information on jaundice, due to an outbreak of jaundice induced by the new yellow fever vaccine. [To learn more about yellow fever vaccine, visit the Wilbur Sawyer Papers on Profiles in Science.] Impressed by Kornberg's study, Dyer arranged his reassignment to a research post in the Nutrition Laboratory at NIH in the fall of 1942. His first project involved tracking down a vitamin deficiency in rats induced by sulfa drugs. Studying the vitamins then known--many of which are coenzymes--Kornberg became intrigued by the central role of enzymes in all living processes, and their immense potential for illuminating the mechanisms of cells. In 1945, desiring to pursue studies of the metabolic enzymes involved in adenosine triphosphate (ATP) production, he received leave to spend a year acquiring further biochemistry training with Severo Ochoa at New York University, and six months with Carl and Gerty Cori at Washington University in St. Louis. It was then, he later recalled, that he began a lifelong love affair with enzymes, the large specialized proteins that catalyze all life processes.
Several years before, Kornberg had married the other love of his life, biochemist Sylvy Ruth Levy. They had met at the University of Rochester and became better acquainted at NIH, where Sylvy was working at the National Cancer Institute. Apart from the six years when their sons Roger, Thomas, and Kenneth were small, Sylvy worked full-time in Kornberg's laboratory throughout their long marriage. The children were often with them there outside of school hours, and two of them, Roger and Thomas, also chose careers in biochemistry. Roger Kornberg went on to receive the 2006 Nobel Prize in Chemistry.
After Kornberg returned to NIH in 1947, he established an Enzyme Section within the Institute of Arthritis and Metabolic Diseases, and continued research into the enzymes involved in metabolic respiration. During the next several years he became very adept at identifying and purifying enzymes, and discovered those that make several key components of metabolic respiration cycles. Encouraged by his success with these systems, he turned his attention to finding the enzyme that assembles various chemical building blocks into the nucleic acids: DNA and RNA. He began by working out the synthesis process for the individual nucleotides, units composed of a nitrogenous base (cytosine, adenine, guanine, uracil, or thymine) combined with a sugar (ribose or deoxyribose) and a phosphate group.
In 1953, Kornberg moved to St. Louis to head the Microbiology Department at Washington University School of Medicine. There he continued working on the synthesis of individual nucleotides, and by 1954 had found the enzymes needed to make all four of the nucleotide building blocks for RNA. A colleague at Washington University had meanwhile found the enzyme that makes the thymine nucleotide (which substitutes for the uracil nucleotide in DNA). Now able to make the building blocks, Kornberg and his colleagues began looking for the enzymes that would put them together into RNA or DNA.
Kornberg focused on the synthesis of DNA after learning in 1955 that Severo Ochoa and his colleagues at NYU had apparently created a synthetic RNA from adenosine diphosphate (ADP) (the product ultimately turned out to be not RNA, but a chain very like it). Working with cell extracts of E. coli bacteria and radioisotope tracers, Kornberg found which combinations of the nucleotides and other ingredients resulted in the most rapid synthesis of DNA. By the following year he had found and purified the essential enzyme, DNA polymerase, from E. coli, and was able to synthesize DNA in the lab. The results were published in 1958, and Kornberg received the 1959 Nobel Prize in Physiology or Medicine (shared with Severo Ochoa) for this work.
Shortly before the Nobel Prizes were announced that year, Kornberg had taken up a new position as chair of the new department of biochemistry at the Stanford University School of Medicine in Palo Alto. Stanford had approached him in 1957, offering the unique opportunity to organize and staff the department from the ground up. Kornberg recruited most of his Washington University faculty and staff, and a number of former postdoctoral fellows for Stanford. Retaining the communal laboratory structure and style that they developed in St. Louis, Stanford's department of biochemistry remained a highly productive, tightly-knit group focused mainly on DNA research. Nearly fifty years later, six of the original faculty--Kornberg, Robert Baldwin, Paul Berg, David Hogness, Dale Kaiser, and Robert Lehman--were still there.
In this stimulating environment, Kornberg and his colleagues continued to identify and delineate the workings of various enzymes involved in DNA replication. In 1967 they synthesized a viable virus DNA, an achievement lauded by the press (to Kornberg's dismay) as the "creation of life in a test tube." They subsequently found enzymes responsible for DNA repair and rearrangement, and others responsible for the start and elongation of DNA chains and chromosomes. The enzymes they discovered, which allowed the manipulation of DNA, helped make possible the development of recombinant DNA technology and the engineering of genes and chromosomes.
In 1991, after many decades of research on DNA replication, Kornberg switched his research focus to inorganic polyphosphate (poly P), a phosphate polymer. Poly P is found in every bacterial, plant and animal cell, but its functions were not well understood. Chemists long regarded it as a molecular fossil, a remnant from earlier evolutionary stages. Kornberg found a variety of likely functions for poly P that include regulating cell responses to stress, and factors responsible for motility and virulence in some of the major disease microorganisms.
In addition to his research and administrative duties, Kornberg also taught graduate, medical, and postdoctoral students. With his own and other Stanford departments so closely involved in the early development of recombinant DNA science, he was long interested in building connections between academic scientists and the emerging biotechnology industry. He was a founding partner of an innovative research institute (DNAX Institute of Molecular and Cellular Biology) in 1980, and served on the advisory boards and councils of many university, governmental, and industrial research institutes.
Kornberg published over three hundred scientific papers during his long career, as well as major monographs on DNA replication, a scientific autobiography, an insider's account of the biotechnology industry, and most recently a children's book, titled Germ Stories, based on stories he told his children and grandchildren over the years.
Besides the 1959 Nobel Prize, Kornberg received numerous other honors, including election to the National Academy of Sciences in 1957, election to the Royal Society of London in 1970, and the National Medal of Science in 1979. He received many honorary doctorates, and in 1999 the University of Rochester dedicated the new Arthur Kornberg Medical Research Building in his honor.
Arthur Kornberg died on October 26, 2007 at the Stanford Hospital, of respiratory failure. He was carrying on his lab research until several days before his death.