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Discovered DNA polymerase, the enzyme that switches on DNA replication
Arthur Kornberg, a prolific researcher who described his career as a “love affair with enzymes,” discovered DNA polymerase, an enzyme critical to DNA replication.
For his discovery, Kornberg shared the 1959 Nobel Prize in Physiology or Medicine with Severo Ochoa, who discovered RNA polymerase. Kornberg’s discovery helped to launch the biotechnology revolution. Downstream discoveries include several genetically engineered drugs used to treat cancer, AIDS, viral infections, and autoimmune diseases. It also laid the groundwork for gene sequencing and the development of laboratory techniques such as the polymerase chain reaction, or PCR.
Philip Pizzo, dean of Stanford University School of Medicine, where Kornberg was an active professor emeritus at the time of his death, described Kornberg as “one of the most distinguished and remarkable scientists in American medicine.”
Kornberg was born in 1918 to immigrant parents from eastern Europe who owned a small hardware store in New York. Although he was a precocious student and graduated from high school at the age of 15, he showed no special interest in science early on. According to the National Library of Medicine, Kornberg “collected matchbook covers rather than butterflies.”
After graduating from medical school at the University of Rochester in 1941, Kornberg served as a ship’s doctor on a US Coast Guard vessel—and had frequent quarrels with the ship’s captain. Although he had intended to stay with the coast guard until the second world war was over, he left his position after just one year to take a research post at the National Institutes of Health (NIH) in 1942.
While still in medical school, Kornberg studied Gilbert syndrome, a disorder he himself had. His report, published in 1942, captured the attention of military medical officers and senior medical officers at the NIH who were concerned at the time with an outbreak of jaundice caused by the yellow fever vaccine. They offered Kornberg a research position at the NIH.
Although Kornberg had no formal research training, he took the NIH post and set to work studying fatal blood disorders induced by sulphur antibiotics in rats. Kornberg discovered that they caused folic acid and vitamin K deficiencies. Since many vitamins serve as components of enzymes or co-enzymes, Kornberg decided to study the “philosophy and practice of enzyme purification.” In 1946 he took leave to study with Severo Ochoa at New York University. There, he learnt the painstaking techniques of separating a target enzyme from thousands of other enzymes and proteins.
His interest in the synthesis of co-enzymes led him to an interest in the biosynthesis of nucleic acids and DNA. Even before Crick, Watson, and Wilkins described the structure of DNA, Kornberg’s fascination with enzymes led him to work on the “machinery” that allowed cells to replicate DNA. But the task of isolating the single enzyme responsible for DNA replication was considered so daunting that many scientists thought it impossible at the time.
After leaving the NIH in 1953 to become professor and chair of the department of microbiology at Washington University, Kornberg accomplished the feat: In 1956, he isolated the enzyme now known as DNA polymerase I from Escherichia coli.
But Kornberg’s discovery was nearly overlooked when he submitted his findings to the Journal of Biological Chemistry in October 1957. A row broke out after some of the journal’s referees wrote scathing critiques of his work. One referee insisted on proof that the DNA synthesised by Kornberg actually had genetic activity—a proof not met by most researchers at the time. Kornberg was disgusted by the reviews and withdrew the two papers. He resubmitted them when a new editor took over the journal, and they were published in May 1958.
After becoming chair of the new biochemistry department at Stanford University School of Medicine in Palo Alto, California, in 1959, Kornberg continued to study DNA polymerase. He discovered that the enzyme could not only trigger replication of DNA but also degrade DNA and even repair mismatched nucleotides, thereby averting disastrous errors.
Later work on DNA polymerases by other scientists and Kornberg himself would raise questions about what role DNA polymerase I actually played in DNA replication. But subsequent work by other researchers and two of Kornberg’s sons, Tom and Roger, helped to elucidate the interplay among several DNA polymerases that allows replication, degradation, and repair of DNA. Roger won the 2006 Nobel Prize in Chemistry for unravelling the mechanism for cells to make proteins using genetic instructions.
While at Stanford, where he remained for the rest of his career, Kornberg worked to develop a genetically active DNA. In 1967 he synthesised a form of circular DNA from a small phage that infects E coli. This led President Lyndon Johnson to announce, “Some geniuses at Stanford University have created life in the test tube.” Kornberg was reportedly “dismayed” by the comment and said such a characterisation was inaccurate since viral DNA has no life outside a larger system.
In 1991 Kornberg turned away from his work on DNA replication and began an intensive period of research—which lasted until his death—into inorganic polyphosphate, which he dubbed “Poly P.” This is a polymer of phosphates that are, according to Kornberg, “responsible for motility and virulence in some of the major pathogens.”
He was widely revered for his teaching style and open sharing of research findings. Robert S Fuller, professor of biological chemistry at the University of Michigan, studied under Kornberg from 1978 to 1984 and says that Kornberg built his biochemistry department on “cooperation, collaboration, and the free and open sharing of ideas and reagents.”
Kornberg wrote a number of books, including For the Love of Enzymes: The Odyssey of a Biochemist, and most recently a children’s book, Germ Stories.
Kornberg was married in 1943 to Sylvy Ruth Levy, a biochemist who worked closely with her husband and famously quipped, “I was robbed,” after she learnt that her husband had won the Nobel prize. Levy died in 1986, and Kornberg married Charlene Walsh Levering in 1988. Levering died in 1995. He then married Carolyn Dixon in 1998. He continued his research and teaching activities at Stanford until just a few days before his death.
Arthur Kornberg, (active) professor emeritus Stanford University Medical School, Palo Alto, United States (b 1918; q University of Rochester, Rochester, NY, 1941), died from respiratory failure on 26 October 2007.