Paul Berg

Paul Berg (born 1926) is best known for his development of a technique for splicing together DNA from different types of organisms. His achievement gave scientists a tool for studying the structure of viral chromosomes and the biochemical basis of human genetic diseases.

Paul Berg made one of the most fundamental technical contributions to the field of genetics in the twentieth century: he developed a technique for splicing together deoxyribonucleic acid (DNA)—the substance that carries the genetic information in living cells and viruses from generation to generation—from different types of organisms. His achievement gave scientists a priceless tool for studying the structure of viral chromosomes and the biochemical basis of human genetic diseases. It also let researchers turn simple organisms into chemical factories that churn out valuable medical drugs. In 1980 he was awarded the Nobel Prize in chemistry for pioneering this procedure, now referred to as recombinant DNA technology.

Today, the commercial application of Berg's work underlies a large and growing industry dedicated to manufacturing drugs and other chemicals. Moreover, the ability to recombine pieces of DNA and transfer them into cells is the basis of an important new medical approach to treating diseases by a technique called gene therapy.

Berg was born in Brooklyn, New York, on June 30, 1926, one of three sons of Harry Berg, a clothing manufacturer, and Sarah Brodsky, a homemaker. He attended public schools, including Abraham Lincoln High School, from which he graduated in 1943. In a 1980 interview reported in the New York Times, Berg credited a "Mrs. Wolf," the woman who ran a science club after school, with inspiring him to become a researcher. He graduated from high school with a keen interest in microbiology and entered Pennsylvania State University, where he received a degree in biochemistry in 1948.

Before entering graduate school, Berg served in the United States Navy from 1943 to 1946. On September 13, 1947, he married Mildred Levy and they had one son, John Alexander. After completing his duty in the navy, Berg continued his study of biochemistry at Western Reserve University (now Case Western Reserve University) in Cleveland, Ohio, where he was a National Institutes of Health fellow from 1950 to 1952 and received his doctorate degree in 1952. He did postdoctoral training as an American Cancer Society research fellow, working with Herman Kalckar at the Institute of Cytophysiology in Copenhagen, Denmark, from 1952 to 1953. From 1953 to 1954 he worked with biochemist Arthur Kornberg at Washington University in St. Louis, Missouri, and held the position of scholar in cancer research from 1954 to 1957.

He became an assistant professor of microbiology at the University of Washington School of Medicine in 1956, where he taught and did research until 1959. Berg left St. Louis that year to accept the position of professor of biochemistry at Stanford University School of Medicine. Berg's background in biochemistry and microbiology shaped his research interests during graduate school and beyond, steering him first into studies of the molecular mechanisms underlying intracellular protein synthesis.

During the 1950s Berg tackled the problem of how amino acids, the building blocks of proteins, are linked together according to the template carried by a form of RNA (ribonucleic acid, the "decoded" form of DNA) called messenger RNA (mRNA). A current theory, unknown to Berg at the time, held that the amino acids did not directly interact with RNA but were linked together in a chain by special molecules called joiners, or adapters. In 1956 Berg demonstrated just such a molecule, which was specific to the amino acid methionine. Each amino acid has its own such joiners, which are now called transfer RNA (tRNA).

This discovery helped to stoke Berg's interest in the structure and function of genes, and fueled his ambition to combine genetic material from different species in order to study how these individual units of heredity worked. Berg reasoned that by recombining a gene from one species with the genes of another, he would be able to isolate and study the transferred gene in the absence of confounding interactions with its natural, neighboring genes in the original organism.

In the late 1960s, while at Stanford, he began studying genes of the monkey tumor virus SV40 as a model for understanding how mammalian genes work. By the 1970s, he had mapped out where on the DNA the various viral genes occurred, identified the specific sequences of nucleotides in the genes, and discovered how the SV40 genes affect the DNA of host organisms they infect. It was this work with SV40 genes that led directly to the development of recombinant DNA technology. While studying how genes controlled the production of specific proteins, Berg also was trying to understand how normal cells seemed spontaneously to become cancerous. He hypothesized that cells turned cancerous because of some unknown interaction between genes and cellular biochemistry.

In order to study these issues, he decided to combine the DNA of SV40, which was known to cause cancer in some animals, into the common intestinal bacterium Escherichia coli (E. coli). He thought it might be possible to smuggle the SV40 DNA into the bacterium by inserting it into the DNA of a type of virus, called a bacteriophage, that naturally infects E. coli.

A DNA molecule is composed of subunits called nucleotides, each containing a sugar, a phosphate group, and one of four nitrogenous bases. Structurally, DNA resembles a twisted ladder, or helix. Two long chains of alternating sugar and phosphate groups twist about each other, forming the sides of the ladder. A base attaches to each sugar, and hydrogen bonding between the bases—the rungs of the ladder—connects the two strands. The order or sequence of the bases determines the genetic code; and because bases match up in a complementary way, the sequence on one strand determines the sequence on the other.

Berg began his experiment by cutting the SV40 DNA into pieces using so-called restriction enzymes, which had been discovered several years before by other researchers. These enzymes let him choose the exact sites to cut each strand of the double helix. Then, using another type of enzyme called terminal transferase, he added one base at a time to one side of the double-stranded molecule. Thus, he formed a chain that extended out from the double-stranded portion. Berg performed the same biochemical operation on the phage DNA, except he changed the sequence of bases in the reconstructed phage DNA so it would be complementary to—and therefore readily bind to—the reconstructed SV40 section of DNA extending from the double-stranded portion. Such complementary extended portions of DNA that bind to each other to make recombinant DNA molecules are called "sticky ends."

This new and powerful technique offered the means to put genes into rapidly multiplying cells, such as bacteria, which would then use the genes to make the corresponding protein. In effect, scientists would be able to make enormous amounts of particular genes they wanted to study, or use simple organisms like bacteria to grow large amounts of valuable substances like human growth hormone, antibiotics, and insulin. Researchers also recognized that genetic engineering, as the technique was quickly dubbed, could be used to alter soil bacteria to give them the ability to "fix" nitrogen from the air, thus reducing the need for artificial fertilizers.

Berg had planned to inject the monkey virus SV40-bacteriophage DNA hybrid molecule into E. coli. But he realized the potential danger of inserting a mammalian tumor gene into a bacterium that exists universally in the environment. Should the bacterium acquire and spread to other E. coli dangerous, pathogenic characteristics that threatened humans or other species, the results might be catastrophic. In his own case, he feared that adding the tumor-causing SV40 DNA into such a common bacterium would be equivalent to planting a ticking cancer time bomb in humans who might subsequently become infected by altered bacteria that escaped from the lab. Rather than continue his ground-breaking experiment, Berg voluntarily halted his work at this point, concerned that the tools of genetic engineering might be leading researchers to perform extremely dangerous experiments.

In addition to this unusual voluntary deferral of his own research, Berg led a group of ten of his colleagues from around the country in composing and signing a letter explaining their collective concerns. Published in the July 26, 1974, issue of the journal Science, the letter became known as the "Berg letter." It listed a series of recommendations supported by the Committee on Recombinant DNA Molecules Assembly of Life Sciences (of which Berg was chairman) of the National Academy of Sciences.

The Berg letter warned, "There is serious concern that some of these artificial recombinant DNA molecules could prove biologically hazardous." It cited as an example the fact that E. coli can exchange genetic material with other types of bacteria, some of which cause disease in humans. "Thus, new DNA elements introduced into E. coli might possibly become widely disseminated among human, bacterial, plant, or animal populations with unpredictable effects." The letter also noted certain recombinant DNA experiments that should not be conducted, such as recombining genes for antibiotic resistance or bacterial toxins into bacterial strains that did not at present carry them; linking all or segments of DNA from cancer-causing or other animal viruses into plasmids or other viral DNAs that could spread the DNA to other bacteria, animals or humans, "and thus possibly increase the incidence of cancer or other disease."

The letter also called for an international meeting of scientists from around the world "to further discuss appropriate ways to deal with the potential biohazards of recombinant DNA molecules." That meeting was held in Pacific Grove, California, on February 27, 1975, at Asilomar and brought together a hundred scientists from sixteen countries. For four days, Berg and his fellow scientists struggled to find a way to safely balance the potential hazards and inestimable benefits of the emerging field of genetic engineering. They agreed to collaborate on developing safeguards to prevent genetically engineered organisms designed only for laboratory study from being able to survive in humans. And they drew up professional standards to govern research in the new technology, which, though backed only by the force of moral persuasion, represented the convictions of many of the leading scientists in the field. These standards served as a blueprint for subsequent federal regulations, which were first published by the National Institutes of Health in June 1976. Today, many of the original regulations have been relaxed or eliminated, except in the cases of recombinant organisms that include extensive DNA regions from very pathogenic organisms. Berg continues to study genetic recombinants in mammalian cells and gene therapy. He is also doing research in molecular biology of HIV-1.

The Nobel Award announcement by the Royal Swedish Academy of Sciences cited Berg "for his fundamental studies of the biochemistry of nucleic acids with particular regard to recombinant DNA." But Berg's legacy also includes his principled actions in the name of responsible scientific inquiry.

Berg was named the Sam, Lula and Jack Willson Professor of Biochemistry at Stanford in 1970, and was chairman of the Department of Biochemistry there from 1969 to 1974. He was also director of the Beckman Center for Molecular and Genetic Medicine (1985), senior postdoctoral fellow of the National Science Foundation (1961-68), and nonresident fellow of the Salk Institute (1973-83). He was elected to the advisory board of the Jane Coffin Childs Foundation of Medical Research, serving from 1970-80. Other appointments include the chair of the scientific advisory committee of the Whitehead Institute (1984-90) and of the national advisory committee of the Human Genome Project (1990). He was editor of Biochemistry and Biophysical Research Communications (1959-68), and a trustee of Rockefeller University (1990-92). He is a member of the international advisory board, Basel Institute of Immunology.

Berg received many awards in addition to the Nobel Prize, among them the American Chemical Society's Eli Lilly Prize in biochemistry (1959); the V. D. Mattia Award of the Roche Institute of Molecular Biology (1972); the Albert Lasker Basic Medical Research Award (1980); and the National Medal of Science (1983). He is a fellow of the American Academy of Arts and Sciences, and a foreign member of the Japanese Biochemistry Society and the Académie des Sciences, France. Berg worked as a Professor of Biochemistry at Stanford University.

Further Reading on Paul Berg

Antebi, Elizabeth, and David Fishlock, Biotechnology: Strategies for Life, MIT Press, 1986.

Magill, Frank N., editor, The Nobel Prize Winners: Chemistry, Volume 3: 1969-1989, Salem Press 1990, pp. 1027-1034.

Wade, Nick, The Ultimate Experiment, Walker, 1977.

Watson, James, Recombinant DNA, W. H. Freeman, 1983.

New York Times, February 2, 1975, p. A1; October 15, 1980, p. A1.

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