Arthur Kornberg

Arthur Kornberg

The discovery of DNA (deoxyribonucleic acid) polymerase by Arthur Kornberg (born 1918) provides scientists with the tool they need to make copies of DNA.

Arthur Kornberg discovered deoxyribonucleic acid (DNA) polymerase, a natural, chemical tool which scientists could use to make copies of DNA, the giant molecule that carries the genetic information of every living organism. The achievement won him the 1959 Nobel Prize in medicine or physiology (which he shared with Severo Ochoa). Since his discovery, laboratories around the world have used the enzyme to build and study DNA. This has led to a clearer understanding of the biochemical basis of genetics, as well as new strategies for treating cancer and hereditary diseases.

Kornberg was born in Brooklyn, New York, on March 3, 1918, to Joseph Kornberg and Lena Katz. An exceptional student, he graduated at age fifteen from Abraham Lincoln High School. Supported by a scholarship, he enrolled in the premedical program at City College of New York, majoring in biology and chemistry. He received his B.S. in 1937 and entered the University of Rochester School of Medicine. It was here that his interest in medical research blossomed and he became intrigued with the study of enzymes—the protein catalysts of chemical reactions. During his medical studies, Kornberg contracted hepatitis, a disease of the liver that commonly causes jaundice, a yellowing of the skin. The incident prompted him to write his first scientific paper, "The Occurrence of Jaundice in an Otherwise Normal Medical Student."

Kornberg graduated from Rochester in 1941 and began his internship in the university's affiliated institution, Strong Memorial Hospital. At the outbreak of World War II in 1942, he was briefly commissioned a lieutenant junior grade in the United States Coast Guard and then transferred to the United States Public Health Service. From 1942 to 1945, Kornberg served in the nutrition section of the division of physiology at the National Institutes of Health (NIH) in Bethesda, Maryland. He then served as chief of the division's enzymes and metabolism section from 1947 to 1952.

During his years at NIH, Kornberg was able to take several leaves of absence. He honed his knowledge of enzyme production, as well as isolation and purification techniques, in the laboratories of Severo Ochoa at New York University School of Medicine in 1946, of Carl Cori and Gerty Cori at the Washington University School of Medicine in St. Louis in 1947, and of H. A. Barker at the University of California at Berkeley in 1951. Kornberg became an authority on the biochemistry of enzymes, including the production of coenzymes—the proteins that assist enzymes by transferring chemicals from one group of enzymes to another. While at NIH, he perfected techniques for synthesizing the coenzymes diphosphopyridine nucleotide (DPN) and flavin adenine dinucleotide —two enzymes involved in the production of the energy-rich molecules used by the body.

To synthesize coenzymes, Kornberg used a chemical reaction called a condensation reaction, in which phosphate is eliminated from the molecule used to form the enzymes. He later postulated that this reaction was similar to that by which the body synthesizes DNA. The topic of DNA synthesis was of intense interest among researchers at the time, and it closely paralleled his work with enzymes, since DNA controls the biosynthesis of enzymes in cells.

In 1953, Kornberg became professor of microbiology and chief of the department of microbiology at Washington University School of Medicine in St. Louis. That year was a time of great excitement among researchers studying DNA; Francis Crick and James Watson at Cambridge University had just discovered the chemical structure of the DNA molecule. At Washington University, Kornberg's group built on the work of Watson and Crick, as well as techniques Ochoa had developed for synthesizing RNA—the decoded form of DNA that directs the production of proteins in cells. Their goal was to produce a giant molecule of artificial DNA.

The first major discovery they made was the chemical catalyst responsible for the synthesis of DNA. They discovered the enzyme in the common intestinal bacterium Escherichia coli, and Kornberg called it DNA polymerase. In 1957, Kornberg's group used this enzyme to synthesize DNA molecules. Although the molecules were biologically inactive, this was an important achievement; it proved that this enzyme does catalyze the production of new strands of DNA, and it explained how a single strand of DNA acts as a pattern for the formation of a new strand of nucleotides— the building blocks of DNA.

In 1959, Kornberg and Ochoa shared the Nobel Prize for their "discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid." The New York Times quoted Nobel Prize recipient Hugo Theorell as saying that Kornberg's research had "clarified many of the problems of regeneration and the continuity of life."

In the same year he received the prize, Kornberg accepted an appointment as professor of biochemistry and chairman of the department of biochemistry at Stanford University. He continued his research on DNA biosynthesis there with Mehran Goulian. The two researchers were determined to synthesize an artificial DNA that was biologically active, and they were convinced they could overcome the problems which had obstructed previous efforts.

The major problems Kornberg had encountered in his original attempt to synthesize DNA were twofold: the complexity of the DNA template he was working with, and the presence of contaminating enzymes called nucleases which damaged the growing strand of DNA. At Stanford, Kornberg's group succeeded in purifying DNA polymerase of contaminating enzymes, but the complexity of their DNA template remained an obstacle, until Robert L. Sinsheimer of the California Institute of Technology was able to direct them to a simpler one. He had been working with the genetic core of Phi X174, a virus that infects Escherichia coli. The DNA of Phi X174 is a single strand of nitrogenous bases in the form of a ring which, when broken, leaves the DNA without the ability to infect its host.

But if the dilemma of DNA complexity was solved, the solution raised yet another problem. The DNA ring in Phi X174 had to be broken in order to serve as a template. But when the artificial copy of the DNA was synthesized in the test tube, it had to be reformed into a ring in order to acquire infectivity. This next hurdle was overcome by Kornberg's laboratory and other researchers in 1966; they discovered an enzyme called ligase, which closes the ring of DNA. With their new knowledge, Kornberg's group added together the Phi X174 template, four nucleotide subunits of DNA, DNA polymerase, and ligase. The DNA polymerase used the template to build a strand of viral DNA consisting of 6,000 building blocks, and the ligase closed the ring of DNA. The Stanford team then isolated the artificial viral DNA, which represented the infectious, inner core of the virus, and added it to a culture of Escherichia coli cells. The DNA infected the cells, commandeering the cellular machinery that uses genes to make proteins. In only minutes, the infected cells had ceased their normal synthetic activity and begun making copies of Phi X174 DNA.

Kornberg and Goulian announced their success during a press conference on December 14, 1967, pointing out that the achievement would help in future studies of genetics, as well as in the search for cures to hereditary diseases and the control of viral infections. In addition, Kornberg noted that the work might help disclose the most basic processes of life itself. The Stanford researcher has continued to study DNA polymerase to further understanding of the structure of that enzyme and how it works.

Kornberg has used his status as a Nobel Laureate on behalf of various causes. On April 21, 1975, he joined eleven speakers before the Health and Environment Subcommittee of the House Commerce Committee to testify against proposed budget cuts at NIH, including ceilings on salaries and the numbers of personnel. The witnesses also spoke out against the tendency of the federal government to direct NIH to pursue short-term projects at the expense of long-term, fundamental research. During his own testimony, Kornberg argued that NIH scientists and scientists trained or supported by NIH funding "had dominated the medical literature for twenty-five years." His efforts helped prevent NIH from being ravaged by budget cuts and overly influenced by politics.

Later that year, Kornberg also joined other Nobel Prize winners in support of Andrei Sakharov, the Soviet advocate of democratization and human rights who had been denied permission to travel to Sweden to accept the Nobel Prize in physics. Kornberg was among thirty-three Nobel Prize winners to send a cable to Soviet President Nikolai V. Podgorny, asking him to permit Sakharov to receive the prize.

Kornberg received the Paul-Lewis Laboratories Award in Enzyme Chemistry from the American Chemical Society, 1951, the Scientific Achievement Award of the American Medical Association, 1968, the Lucy Wortham James Award of the Society of Medical Oncology, 1968, the Borden Award in the Medical Sciences of the Association of American Medical Colleges, 1968, and the National Medal of Science, 1980. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, the American Society of Biological Scientists, and a foreign member of the Royal Society of London. In addition, he is a member of the American Philosophical Society and, from 1965 to 1966, served as president of the American Society of Biological Chemists. In 1995, he published a book The Golden Helix: Inside Biotech Ventures. Kornberg has been married to Sylvy Ruth Levy Kornberg since 1943. His wife, who is also a biochemist, has collaborated on much of his work. They have three sons.

Further Reading

Wasson, Tyler, editor, Nobel Prize Winners, H. W. Wilson, 1987, pp. 797-802. □