Kornberg, Arthur
Mar. 3, 1918-Oct. 26, 2007
American biochemist
Science moved a giant stride closer to the possibility of creating life in a test tube when, in 1967, a team of biochemists headed by Dr. Arthur Kornberg at the Stanford University School of Medicine succeeded in synthesizing biologically active DNA, or deoxyribonucleic acid, outside of a living cell. DNA, the substance of which genes are made, is the chemical bearer of all hereditary characteristics, the genetic template that determines the pattern of growth and development of every living thing. The creation of artificial DNA by Kornberg, in collaboration with Dr. Mehran Goulian, now at the University of Chicago, and Dr. Robert L. Sinsheimer, at the California Institute of Technology, brings nearer the day when man may control virus diseases and cancer through manipulation of the nucleotides, the building blocks of the genetic code.
Kornberg's first success with artificial DNA came in 1957, when he produced a chemically exact but genetically inert replica of the natural substance. For that earlier achievement he shared the 1959 Nobel Prize in medicine and physiology with Dr. Severo Ochoa. Before going to Stanford, where he is executive head of the department of biochemistry, Kornberg pursued his research at Washington University in St. Louis and at the National Institutes of Health (NIH) in Bethesda, Maryland. The major financial subsidies for his work have come from the NIH and the National Science Foundation.
Arthur Kornberg was born in Brooklyn, New York on March 3, 1918 to Joseph and Lena (Katz) Kornberg. He attended local public schools, achieving a brilliant scholastic record and graduating from Abraham Lincoln High School in June 1933, a few months after his fifteenth birthday. On a New York State scholarship, he took a pre-medical course at the College of the City of New York. Upon receiving his B.S. degree with honors at CCNY, in 1937, he went on a Buswell scholarship to the University of Rochester School of Medicine, where he became interested in enzymes-the organic protein juices that serve as catalysts in cell reactions essential to the life processes-and he decided to devote himself to enzyme research instead of medical practice. While at Rochester he published his first scientific paper, "The Occurrence of Jaundice in Otherwise Normal Medical Students."
After taking his M.D. degree at the University of Rochester, in 1941, Kornberg interned for one year at Strong Memorial Hospital in Rochester. In 1942 he served briefly as a medical officer with the rank of lieutenant junior grade in the United States Coast Guard, and in the same year he was commissioned an officer in the United States Public Health Service and assigned to the National Institutes of Health in Bethesda, Maryland. At NIH he worked in the nutrition section of the physiology division from 1942 to 1945, and he was chief of the enzymes and metabolism section from 1947 to 1952.
From the beginning of his research Kornberg was interested not only in what enzymes are and what they do but in a more fundamental genetic mystery: how and why a particular cell produces this or that enzyme and no other. Aside from clues provided by the work of such men as Friedrich Miescher, in 1869, and Frederick Griffith, in 1928, little was known about the biochemistry of genetics until the mid-twentieth century, when a rapid series of developments took place. In 1941 George Beadle and Edward Tatum at Stanford University demonstrated that the genes control the processes of life by chemical means. Three years later Dr. Oswald T. Avery and his associates at Rockefeller Institute in New York City isolated the chemical substance in question and found it to be, not protein, as had been supposed, but the nucleic acid DNA. Later research, particularly that conducted by James D. Watson and Francis Crick at Cambridge University in England, provided a detailed description of DNA. Located in the nucleus of the cell, in the genes that are strung along the chromosomes, it is composed of some sugar, some phosphate, and, most important, the "letters" of the genetic alphabet, the nitrogenous bases A (adenine), C (cytosine), G (guanine), and T (thymine), also known as nucleotides. A gene is a stretch of DNA that contains 1,000 or more of those letters or building blocks spelling out a recipe for a particular genetic trait. If the arrangement or configuration of the nitrogen building blocks is shuffled, the genetic message is changed. Individually, molecules of DNA have the function of serving as templates, or molds, for the production of exact copies of themselves, so that the cell may endow its offspring with identical coded information. Together, they specify in the thousands of genes that make up an animal chromosome the full chemical detail of the enzymes needed for the fabric and machinery of the cell, and ultimately they determine whether the organism shall be a paramecium or an anthropoid. Another master chemical of life, RNA (ribonucleic acid), located mostly in the cytoplasm surrounding the cell's nucleus, translates the DNA code into the production of appropriate protein.
On leaves of absence from the NIH, Kornberg increased his knowledge of enzymes and his experience in their production, isolation, and purification by working with Carl and Gerty Cori at the Washington University School of Medicine in St. Louis, with H. A. Barker at the University of California at Berkeley, and with Severo Ochoa at the New York University College of Medicine. Ochoa became the first scientist to synthesize RNA, in 1956, and it was for that achievement that he later shared the Nobel Prize with Kornberg.
In 1953 Dr. Kornberg left the National Institutes of Health to become head of the department of microbiology at the Washington University School of Medicine. Taking the Watson-Crick model of the DNA molecule as a guide, and using techniques roughly similar to those employed by Dr. Ochoa in synthesizing RNA, Kornberg and his associates at Washington University set out to produce a giant molecule of artificial DNA. Three things were needed: pre-existing DNA as a template to be copied; the nucleotides A, T, G, and C; and an enzyme to select and arrange the nucleotides according to directions from the template and to link them together to form the DNA chain. In 1956, experimenting with enzymes from other bacteria, they isolated and purified the enzyme DNA polymerase from the common intestinal variety of bacteria called Escherichia coli. The following year, using the DNA polymerase as enzyme, they succeeded in producing a giant molecule of artificial DNA that lacked the genetic properties of natural DNA but had its chemical and physical characteristics.
At the Stanford University School of Medicine in Palo Alto, California, where he became executive head of the department of biochemistry in 1959, Kornberg, assisted by Dr. Mehran Goulian, stepped up his efforts to produce a biologically active molecule of artificial DNA. The chief problem encountered in his previous research had been the complexity of the DNA template in combination with the impurity of the enzyme. Extraneous nucleases had damaged the DNA polymerase, causing it to dictate critical errors in the arrangement of the nitrogen bases, with the result that the artificial DNA could not do the work of the natural substance. Dr. Robert L. Sinsheimer of the California Institute of Technology provided Kornberg and Goulian with a new, simpler template, the genetic core of the dwarf virus Phi X174, which preys on Escherichia coli. The Phi X174 DNA is single-stranded, in the form of a ring, and its infectivity is lost when the circle is broken. In addition to purifying the DNA polymerase used in Kornberg's earlier experiments, Kornberg and Goulian had to find another enzyme-one with polynucleotide-joining properties sufficient for closing the Phi X174 DNA ring. Such an enzyme, ligase, was discovered-simultaneously by Kornberg and his associates at Stanford and by other laboratory teams elsewhere-in 1966.
Using the natural DNA of the Phi X174 virus as a template, Kornberg and his associates added the four nucleotides, the enzyme DNA polymerase, and the enzyme ligase to the test tube. The DNA polymerase ordered the nucleotides in the arrangement dictated by the template, and the ligase closed the ring of DNA thus reproduced. With a centrifuge, Kornberg separated the synthetic from the natural DNA. When the synthetic substance was added to a culture of Escherichia coli cells it infected them and usurped the genetic machinery. Within minutes the cells had abandoned their normal activity and were busy producing Phi X174 viruses. The synthetic DNA had become a template for a second generation of synthetic viruses identical to the original. The sequence of the 6,000 building blocks, and the arrangement of the thirty-five atoms within each, was precisely the same in the artificial substance as in the natural one. If one of the blocks had been out of place, the artificial DNA would have been biologically inactive. Dr. Sinsheimer at Cal Tech tested the synthetic DNA and confirmed that it was fully virulent, entering cells and producing new viruses just as efficiently as DNA from natural sources.
Goulian and Kornberg announced their success in artificially producing the active, infectious inner core of a virus in a news conference held on December 14, 1967, simultaneous with publication of a full report in the December 1967 issue of the Proceedings of the National Academy of Sciences. They pointed out the significance of the achievement in opening the way to future progress in the study of genetics, the curing of hereditary defects, and the control of disease, particularly virus infections and cancer. "If we know how to use this enzyme to copy this particular virus, then we can copy other viruses," Kornberg told an interviewer. "And we can copy them in ways in which we can modify their structure by putting in alternative or fraudulent building blocks to create new forms of virus. We can then use the synthetic virus to infect cells and produce altered responses…. I think it is reasonable to expect that the polyoma viral DNA [a common cause of cancer in animals] will be synthesized by an enzyme system. With such a synthetic system we should be on our way toward figuring out what genes in the virus are responsible for the cancer response." Once the genes are identified, he pointed out, steps can be taken to alter them. He also suggested that synthetic viruses could play an important role in fighting some forms of mental retardation and other ailments in which the genes are involved.
Kornberg told the interviewer that his research in the immediate future would take two general directions: "One direction is to understand in finer chemical detail the enzyme catalyst called DNA polymerase, which assembles the DNA chain…. If we are to understand how this enzyme works in the cell, in health or disease, during growth or aging, we must first figure out how it works in the simpler and more accessible test tube system. The other direction of our work is to understand what regulates DNA synthesis in the cell. When growth stops in a mature person, DNA synthesis in his liver cells also stops. However, if a portion of the liver is removed by surgery … [or] when liver cells turn cancerous, DNA synthesis proceeds rapidly, as it does in the young growing liver. We are at a loss to understand the forces that keep liver DNA synthesis in check in the normal adult and the agents that provoke DNA synthesis in cancer growth."
At the end of the interview Kornberg said that he hoped his work would have little influence on human evolution, at least in the immediate future. "There is vastly more we can and must do to further human cultural evolution by political and social means," he explained. "I see the greatest rewards of genetic chemistry to human welfare in the cure of disease and ultimately in a better understanding of human behavior when explained in terms of chemistry."
Arthur Kornberg and Sylvy Ruth Levy, a biochemist, who collaborates in much of her husband's work, were married on November 21, 1943. They have three sons, Roger, Thomas, and Kenneth. The Kornbergs live in Portola Valley on the San Francisco Peninsula. Dr. Kornberg is a quiet man of medium height and athletic build whose smile has been described as "gentle." His favorite physical recreations are swimming and playing tennis. In spectator sports he is a football buff, a fan of the San Francisco giants and the Stanford football team. Honors received by Kornberg in addition to the Nobel Prize include the Paul-Lewis Award of the American Chemical Society and honorary degrees from the College of the City of New York, the University of Rochester, Yeshiva University, Washington University (St. Louis), and the University of Notre Dame. He served as president of the American Society of Biological Chemists in 1965-66, and he is a member of the American Philosophical Society, the National Academy of Sciences, and the Phi Beta Kappa, Alpha Omega Alpha, and Sigma Xi fraternities. Other professional organizations to which he belongs are the American Society for Clinical Investigations, the American Chemical Society, and the Harvey Society. Besides his scientific papers, Kornberg is the author of Enzymatic Synthesis of DNA, published by Wiley in 1962.
