Werner Arber Biography (1929-)

molecular biologist

Werner Arber's discovery of an enzyme that could cleave long strands of deoxyribonucleic acid (DNA) led to a revolution in genetics research, providing the foundation that led to techniques to separate and reassemble basic geneticmaterial. Gene splicing, as it was called, proved invaluable for DNA sequencing and gene mapping, which focuses on genetic organization. The most controversial outcome of this research, however, was the eventual manipulation of DNAstructures by geneticists, first in test tubes and then in vivo, orwithin a living organism. Arber received the 1978 Nobel Prize in physiologyor medicine for his research on gene splicing, sharing the prize with UnitedStates scientists Hamilton O. Smith and Daniel Nathans, who hadalso played an essential role in the development of gene splicing. A devotedfamily man, Werner eschewed politics but was well aware of the implicationsof genetic manipulation and warned his fellow scientists that such genetic research should be used carefully. As a result, Arber conducted studies and participated in symposia on how to prevent the unintentional release of a genetically altered virus into the environment.

Werner Arber was born in Gränichen, Switzerland, on June 3, 1929. Educated in the Swiss public school system, he entered the Federal Institute of Technology in Zurich in 1949, where he focused on the natural sciences. Arber soon became exposed to experimental research and embarked on studies to isolateand characterize the radioactive isotope of chlorine. After graduation in 1953, he entered the University of Geneva as a graduate student, received an appointment as a research assistant in a laboratory, and studied biophysics. Werner became interested in bacterial viruses (bacteriophages) through the biophysicist Jean J. Weigle's studies of variations in these viruses, which aimedto show that a specific bacteriophage will only infect a specific host. Another biophysicist, Salvador Edward Luria, showed that when phages infect a different strain of bacteria, a few survive to plate efficiently with thenew host strain. Most of the phages die out, and the surviving phages are nolonger capable of infecting an earlier host. The phenomenon was first calledhost-induced variation and is now commonly known as host-controlled restriction-modification.

During his graduate studies, Arber assisted biophysicists at Geneva in developing high-level magnification techniques in electron microscopy to study bacteriophages. He completed his dissertation on deficiencies of a mutant strainof bacteriophage lambda and received his Ph.D. in 1958. Arber then went to the University of Southern California for further study and to refine his laboratory techniques in genetics and bacteriophage research. While in the UnitedStates, Arber also took the opportunity to visit several colleagues who werestudying bacteriophages.

Arber returned to Switzerland to join the faculty at the University of Genevain 1960. With support from the Swiss National Science Foundation, he embarked on studies of the molecular basis of bacteriophage restriction. Working with one of his graduate students, Daisy Dussoix, Arber found in 1962 that restriction was host-controlled and involved changes in the phage's DNA. In effect, the DNA of the invading phages is cut into component parts, although some phages survived the operation. This discovery set in motion a series of studies that jump-started genetics to become the new frontier in biomedical research.

Arber himself formulated a hypothesis presupposing that an endonuclease enzyme in the host severs the DNA of invading phages into component parts, while amethylase enzyme modifies the DNA of the host to make it invulnerable to itsown endonuclease enzyme. Although he had yet to discover such an enzyme, Arber hypothesized that an endonuclease recognizes specific sequences of nucleotides, a fundamental building block of DNA and RNA, and cuts the DNA of the invading phages at the specific locations of these nucleotides. Arber called this two-enzyme theory a restriction-modification system. The theory received initial confirmation when Arber, with the biophysicist Urs Kühnlein, isolated phage mutants that were inert to restriction and modification by mutation at specific nucleotide recognition sites. This discovery directly correlated Kühnlein's observation of DNA methylation with host-controlled modification in phages.

In 1965 Arber was appointed extraordinary professor of molecular genetics atthe University of Geneva. He continued his research on restriction-modification and discovered, in 1968, the restriction endonuclease of Escherichia coli B, a common gut bacterium widely used in genetic studies. (At the same time Matthew Meselson and Robert Yuan identified the endonuclease from Escherichia coli K.) Although Arber's enzyme recognized specificnucleotide sequences, it cut the DNA at random spots and would later be known as a Type I restriction endonuclease. Since these Type I endonucleases severed the DNA at areas away from the recognition sites, they were unsuitable for studies of gene splicing. The second part of Arber's theory--that the endonuclease cut the invader's DNA at specific sites--was confirmed by the microbial geneticist Hamilton Smith and his colleagues, K. W. Wilcox and Thomas J. Kelley. Working at Johns Hopkins University, they identified what eventually came to be known as Type II, or specific, endonuclease. Daniel Nathans, also at Johns Hopkins, was a cancer researcher who first identified elevencleaved fragments of a simian (monkey or ape) virus and eventually deduced the order in which individual fragments were replicated, showing that they began at a specific site and went in both directions around a circle, stopping approximately 180 degrees from where they started. Nathans and colleagues wenton to isolate messenger RNA (mRNA), a type of RNA that is complementary to the protein-encoding segments of the host strand of DNA and communicates genetic information to proteins. They then began to map transcription sites (the origin and direction of each mRNA transcript during infection) by looking at different stages of infection and testing the RNA's ability to hybridize to the various "restriction fragments" due to their nucleotide sequences. This pioneering research led to a barrage of genetic studies aimed at mapping geneticcodes, culminating in the international human genome project, which geneticists began in the late 1980s to develop a comprehensive road map of the humangenetic system. Over the years, geneticists built upon the work of Arber, Smith, and Nathans to develop techniques to produce enough of a particular geneto study and then to artificially alter DNA through the transfer or insertionof genetic material.

Arber eventually became dissatisfied with what he perceived to be academic politics and the dearth of students devoting themselves to research careers atthe University of Geneva. He left the university in 1970 and spent a year atthe University of California at Berkeley as a visiting professor in the Department of Molecular Biology. Upon returning to Switzerland, he took an appointment as ordinary professor of molecular biology at the University of Basel and was reserved extensive modern facilities in the Biozentrum research institute, which was then under construction.

In 1978, Arber, Smith, and Nathans won the Nobel Prize for physiology or medicine, Arber being noted for his research showing that the host can alter DNAto prevent invasion by phages and other foreign genes through methylation (combining DNA with two carbons and three hydrogens), which cleaves the DNA. Thecumulative efforts of these three scientists were an example of the growingemphasis on interdisciplinary communication and cooperation in scientific research as new discoveries in genetics were made simultaneously at many institutions throughout the world.

Arber's subsequent research has focused on genetic systems and their diversification. With the confirmation in the 1970s of Barbara Mc Clintock's theories of transposable genes that could "jump" to different strands of DNA during the early stages of meiosis (the process of cell division), Arber and other geneticists began to experiment with gene transplantation. Arber has theorized that genetic exchange through transposition may account for the diverse bacterial genetic codes that occur during evolution.

Investigations into recombinant DNA technology, however, also had controversial aspects. Studies of combining eukaryotic DNA (that is, DNA from an organism consisting of more than one cell) with bacterial or viral DNA in a moleculeraised concerns about producing pathogens (a micro-organism that can carry disease), especially since these pathogens could be cloned by copying the DNAmolecules. Arber participated in discussions that led to a set of guidelinesdeveloped by the National Institutes of Health to conduct recombinant DNA research safely. As Arber points out in his introductory paper for the proceedings of the symposium, Genetic Manipulation: Impact on Man and Society, the initial risk was faced by the experimenters themselves, who were in direct contact with potential pathogens. What concerned the public, however, wasthe possibility of potential pathogens being accidentally introduced into the environment. Arber called for a realistic evaluation of the risks, saying that the guidelines had been designed to reduce the risks to a minimum.

Because of these precautions, geneticists have avoided serious mishaps and developed remarkable recombinant DNA studies, including a promising biomedicalapplication known as gene therapy. Gene therapy begins with the splicing of DNA segments from various origins into a vector DNA molecule. Vectors act as "molecular delivery trucks," carrying genes to targeted cell types or organ systems, and are carefully chosen for their ability to colonize certain cell types and tissues in the body and become an inheritable trait. In gene therapy,disease-causing genes (specific nucleotide sequences) are replaced with normal sequences or additional genetic material is inserted to change the genes.This genetic material, for example, could carry a gene that expresses an inhibitor of a certain protein or hormone that causes a disease, such as arthritis. Investigators have also focused on gene therapies for cancer.

Arber married his wife, Antonia, in 1965. They have two daughters. Outside ofhis scientific pursuits, Arber has devoted his time to his family, who strongly support his scientific efforts.

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