American biochemist Paul Berg has been making outstanding contributions to biochemistry and molecular biology for over fifty years. As a young researcher he resolved several key problems in metabolic chemistry, and went on to discover the mechanisms by which DNA and RNA direct the synthesis of proteins in living systems. In 1972, he and his colleagues at Stanford University synthesized the first recombinant DNA (rDNA), and he subsequently led the international community of rDNA researchers in their efforts to address the potential physical and ethical hazards posed by that revolutionary technology. He received the 1980 Nobel Prize in Chemistry for his protein synthesis and rDNA work, and has continued to elucidate genetic mechanisms, using specially designed recombinant organisms.
Berg was born in Brooklyn, New York, on June 30, 1926, the eldest of Harry and Sarah Berg's three children. Interested in biology from an early age, he was motivated to pursue a research career when he read Sinclair Lewis's Arrowsmith and Paul deKruif's The Microbe Hunters in junior high school. He entered Lincoln High School at age 14, having skipped a grade in elementary school. At Lincoln High his scientific ambitions were further stimulated by Sophie Wolfe, who supervised the science supply room and mentored the Biology Club. Though not a classroom instructor, Wolfe had a profound influence on Berg and other science students, giving them innovative problems and projects to work on, nurturing their curiosity, and showing them the joy of seeking and finding solutions to complex questions.
Berg graduated high school in January 1943, and, eager to join the war effort, enlisted in the Navy as soon as he turned 17 that June. While waiting to be called up for Navy flight school, he enrolled in the biochemistry program at Pennsylvania State University, where he also did his pre-flight training. When the Navy cut back on fighter pilot training, he trained instead for ship duty and served until 1946 on submarine chaser ships. He then returned to Penn State to continue his biochemistry studies and received his BS in 1948. The previous year he had married Mildred Levy, whom he had known since they met through a summer job in high school; they later had one child, John.
Berg had intended to pursue a research career in the pharmaceutical industry, but during his senior year at Penn State he became interested in the emerging use of radioactive isotopes for tracing metabolic reactions. He determined to work for a PhD in biochemistry and did his graduate work with a leading investigator in that area, Harland O. Wood, at Western Reserve University (now Case Western Reserve University) in Cleveland, Ohio. Berg's doctoral research solved a central problem in biochemistry by demonstrating how vitamin B-12 and folic acid enabled animals to synthesize the amino acid methionine (earlier believed to be available only through their diets). This work also led him to pursue further training in enzymology to aid his investigations into metabolic chemistry. He had met two rising stars in enzyme chemistry, Arthur Kornberg and Hermann Kalckar, when they visited Western Reserve, and asked to do postdoctoral work with them. After receiving his PhD in 1952, he spent a year with Kalckar at the Institute of Cytophysiology in Copenhagen, where he and another postdoctoral fellow, hoping to clarify a key step in glucose metabolism, instead discovered a new enzyme that makes possible the transfer of phosphate groups from adenosine triphosphate (ATP--the principal energy-carrying molecule in living systems) to similar energy-carrying molecules such as inosine triphosphate (ITP) or guanosine triphosphate (GTP). The work suggested that biological systems could use triphosphate forms other than ATP to carry energy.
Berg spent the 1953-1954 academic year in Arthur Kornberg's lab at the Washington University School of Medicine in St. Louis. He chose to pursue a problem regarding the synthesis of acetyl-substituted Co-enzyme A (acetyl-SCoA), an essential intermediate product in the central metabolic process that breaks down food to produce usable energy. Fritz Lippmann and Feodor Lynen had proposed a three-step process that included a AMP-enzyme complex. Berg purified the enzyme but then discovered that instead of forming a complex with AMP, the enzyme catalyzed acetyl-SCoA synthesis by a completely different pathway. This work disproved the model proposed by the two eminent biochemists, and solved another important problem in the field. Later investigations showed that fatty acid metabolism and synthesis operated via similar chemical processes.
Berg stayed on at Washington University and was appointed assistant professor in 1956. His subsequent research demonstrated that the mechanism by which amino acids are assembled into proteins was very similar to that observed in fatty acid synthesis, i.e., amino acids are "activated" into an acyl-AMP form, so they can be attached to transfer RNA (tRNA). Transfer RNAs then transport them to cell ribosomes for protein assembly. He received the 1959 Eli Lilly Prize in Biochemistry for this work, and his subsequent research focused increasingly on RNA-directed protein synthesis and how genes operate in the process.
In 1959 Arthur Kornberg moved most of the Washington University department, including Berg, to a new biochemistry department at Stanford University School of Medicine. By that time, Berg had made the transition from classical biochemistry to molecular biology. At Stanford, he and his colleagues discovered how specific enzymes in bacteria "activated" each amino acid for transfer by tRNA and then assembly into proteins, and how mutations can affect that process.
In the mid-1960s, Berg became interested in possible analogies between the workings of bacterial viruses ("phages"), long studied by biologists, and those of the tumor viruses that infect some mammalian cells. Hoping to discover whether viruses could be used to study gene regulation in mammalian cells, as they had been in bacteria, he spent a sabbatical year learning cell culturing methods with Renato Dulbecco at the Salk Institute. When he returned to Stanford, he began investigating how mammalian viruses might pick up genes and transfer them to new cells as bacterial viruses often did. Tumor viruses were too small to act as vectors, so Berg and his colleagues engineered a virus for the purpose. The technique they developed in 1971-72 for splicing two DNA molecules--one from a tumor virus and one from a plasmid carrying E. coli genes--marked the beginning of recombinant DNA (rDNA) technology. In 1980, Berg received the Nobel Prize and the Lasker Award for this work.
By 1973, the development of a simpler rDNA technique by Stanley N. Cohen and Herbert Boyer raised concerns in the scientific community about the potential hazards of engineered microbes, e.g., combining tumor virus genes with those from a common intestinal bacteria. This led Berg and others to request a voluntary moratorium on rDNA research in 1974, pending organized discussions of the risks and how they might be contained. Berg and NIH scientist Maxine Singer organized and chaired the Asilomar Conference on Recombinant DNA, held at the Asilomar Conference Center in Pacific Grove, California, in February 1975. Attended by an international group of 150 scientists, along with a panel of lawyers and journalists, the conference proposed to formulate recommendations for rDNA research guidelines. The conference recommendations were then taken up by a committee at the National Institutes of Health (NIH), chaired by NIH director Donald Fredrickson, which issued formal guidelines the following year. As scientists gained experience in working with recombinants, the initial restrictions were relaxed. Berg has continued to be an activist in public policy issues affecting the biomedical sciences, including rDNA and more recently, embryonic stem cells.
Berg expanded his rDNA research between 1980 and 2000, investigating, among other things, the mechanism of recombinational repair of damaged DNA. Recognizing a need to connect molecular biology researchers more closely with clinical researchers, he helped establish the multidisciplinary Beckman Center for Molecular and Genetic Medicine at Stanford in 1985, and served as its first director.
Like many genetics researchers, Berg has built connections between academic and industrial researchers. With his colleagues Arthur Kornberg and Charles Yanofsky, he founded DNAX, a biotechnology research institute, in 1980. The initial focus of research at DNAX was to use rDNA to design immunoglobulins (immune system antibodies) with special properties. After Schering-Plough acquired the institute, research was shifted to production of interleukins (non-antibody types of immune system elements), using an expressive cloning system developed in Berg's lab. Since its establishment, DNAX has developed into one of the leading research centers for immunology.
Dr. Berg has published over 200 scientific articles, and, with Maxine Singer, has written several books on genetics for non-scientists. In 2003, he and Singer published a biography of pioneering geneticist George Beadle (George Beadle: An Uncommon Farmer). In addition to the 1980 Nobel Prize and Lasker Award, he has received numerous other honors and awards, including election to the National Academy of Sciences in 1966, the National Medal of Science and election to the American Philosophical Society in 1983, election to the Royal Society in 1992, and four honorary doctorates. A gifted teacher, he received Stanford University School of Medicine's Henry J. Kaiser award in 1969 and again in 1973.