The 2003 GSA Honors and Awards

The 2003 Thomas Hunt Morgan Medal

The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt Morgan Medal recognizes a lifetime contribution to the science of genetics. The Genetics Society of America Medal recognizes particularly outstanding contributions to the science of genetics within the past 15 years. The George W. Beadle Medal recognizes distinguished service to the field of genetics and the community of geneticists. We are pleased to announce the 2003 awards.

AT a time when genomics is adding new dimensions to the molecular characterization of life, it is fitting that David Swenson Hogness be recognized by the Genetics Society of America with the 2003 Thomas Hunt Morgan Medal, for a lifetime of contributions to the field of molecular genetics. Modern genome analysis was founded in 1972 by Hogness when, in anticipation of the first successful recombinant DNA cloning of eukaryotic DNA a year later, he proposed in a grant application the concepts and basic methodology for producing "libraries" of genomic DNA, for producing physical maps of overlapping clones covering entire chromosomes, and for isolating mutant genes solely on the basis of their position on chromosomes (a technique that later came to be known as "positional cloning"). Over the next decade, the Hogness lab successfully implemented his revolutionary proposals by producing the first random genomic clones from any organism, mapping the first cloned DNA segment to a specific chromosomal location, producing the first recombinant DNA clone library representing an entire genome, and screening that library for clones that carried specific sequences using a novel filter hybridization method called "colony hybridization." These achievements were followed by the first chromosomal "walk" and use of chromosomal rearrangements to achieve the first positional cloning of any gene. This was followed by the mapping of mutant alleles and transcripts on a genomic DNA map of over 300 kb, representing a first example of what we now call "functional genomics."

During his career, Hogness made important contributions using three model genetic organisms: Escherichia coli, bacteriophage , and Drosophila melanogaster. In Jacques Monod's laboratory, Hogness and Melvin Cohn showed for the first time that enzyme induction in bacteria results from an increase in the rate of the de novo synthesis of an enzyme from its constituent amino acids. This was fundamental groundwork for Monod's subsequent studies on inducible promoters that led to Jacob and Monod's operon model for gene regulation in bacteria. After moving to St. Louis, Hogness began his studies of the genetic organization of bacteriophage and its derivative dg. With A. D. Kaiser, he invented a transformation assay for the activity of genes contained in purified phage DNAs and in terminal fragments containing either the "left" or "right" ends. Using this assay to determine the gene content of both left and right terminal fragments, Hogness and his colleagues generated the first physical maps of genes in DNA. Comparison of these physical maps with genetic recombination maps demonstrated their colinearity for the first time. Other experiments in the Hogness lab involving the isolation of each of the two strands of these phage DNAs provided a means of orienting the genes on the map according to the direction of their transcription.

In 1968 Hogness changed the focus of his research from the genome of to that of higher eukaryotes, and in particular that of D. melanogaster. He spent a sabbatical year in the laboratories of Edward B. Lewis (Caltech), James Peacock (CSIRO, Canberra), and Wolfgang Beerman (Max-Planck-Institut, Tübingen) learning about Drosophila and polytene chromosomes, with an aim of carrying out molecular genetic analyses of Drosophila and its development at the same level as he had for . During the early part of this transition, his laboratory solved the problem of how the long chromosomal DNAs of Drosophila can replicate as fast as the shorter genome of . This was achieved by an electron microscopic determination of the distribution of replication origins in rapidly replicating Drosophila DNA.

In an NIH grant application in 1972 Hogness presented revolutionary plans for what is now called "genomics"—plans that included production of recombinant DNA libraries representing entire chromosomes or genomes, ordering of overlapping genomic clones to produce physical maps of entire chromosomes, the use of these chromosomal "walks" together with chromosome rearrangements to positionally clone genes identified solely on the basis of their mutant phenotype and genetic map position (positional cloning), and subsequent mapping of mutations and transcripts (what we now refer to as functional genomics).

This proposal was soon implemented in his laboratory. By 1973 small libraries of randomly cloned segments of Drosophila genomic DNA were obtained, the first such libraries for a higher eukaryote. The properties of some of these cloned DNA segments were reported in 1974, including their content of single-copy and repetitive sequences and the location of these sequences within the genome, work that led to the first molecular identification of transposable elements. The first clonal-hybridization method for identifying clones containing specific sequences, colony hybridization, was reported by the Hogness laboratory in 1975. This technique was first used in Hogness's laboratory for the analysis of rDNA and histone genes in Drosophila. Analysis of the first of these led to the discovery of interrupted eukaryotic genes. Analysis of the sequences immediately upstream of the histone genes carried out by Hogness while on sabbatical in Walter Gehring's laboratory resulted in discovery of the "Goldberg-Hogness box," now known as the TATA box. In 1978–1979, techniques were developed by Hogness and his colleagues to allow genes to be cloned solely on the basis of their position in the genome relative to sequences that had been isolated previously. At a truly seminal National Drosophila Meeting held in San Diego in 1987, Hogness shared a session with Ed Lewis in which Hogness described the application of this strategy in terms of his progress on cloning the Ultrabithorax gene. This approach, which was originally called "chromosome walking and jumping," is now better known as positional cloning, a method widely used in all genome mapping projects to clone genes that have been identified only by mutations that lie within them.

These methods were subsequently expanded by Hogness into what we now call functional genomics: the correlation of physical maps of chromosomes with genes, mutations, and transcribed regions (and, ultimately, the complete sequence of each region). To accomplish this, Hogness and colleagues studied the structure and function of the homeotic genes that specify the identity of cells in different body segments during Drosophila development. His positional cloning of the Ultrabithorax gene (Ubx) of the bithorax complex of D. melanogaster allowed Hogness and his colleagues to map mutations defining this gene and to identify its transcription unit, its mRNA sequences, and its large cis-regulatory regions. This revealed that, despite the complex phenotypes associated with mutations in this gene, Ubx comprises one long protein-encoding transcription unit and two large cis-regulatory regions rather than several protein-encoding genes as had been previously thought. Many of the complex phenotypes associated with mutations in the bithorax complex were shown to be due to changes affecting these regulatory regions rather than the protein-coding sequence. This is an important principle that is now known to apply to the other seven homeotic genes in the bithorax and Antennapedia complexes. The coding capacity of Ubx is also complex as alternative splicing of Ubx transcripts gives a set of protein isoforms expressed at different times and in different tissues and having different functions.

While the Ubx gene served as a model system for investigating the structure and function of regulatory genes, Hogness used a second model system to investigate the molecular nature of genetic regulatory hierarchies. The timing and process of metamorphosis in Drosophila is regulated by the steroid hormone ecdysone, which triggers a complex series of events that may differ from one tissue to another. Earlier work by M. Ashburner and others had suggested that these complex responses reflect hierarchies of genes whose expression is affected by ecdysone. Over a period spanning three decades, the Hogness lab isolated and studied genes encoding the ecdysone receptor, primary response genes whose transcription is directly regulated by the ecdysone-receptor complex, and secondary response genes whose expression is regulated by the transcription factors encoded by the primary response genes. The complex interactions between differentially expressed isoforms of the receptor, the diversity of the primary response genes, and the tissue-specific functions of the secondary response genes have provided an outstanding model for understanding the relationship between gene expression and the control of developmental processes.

A Festschrift held at Tomales Bay, California, in 1995 brought together for a few days almost all of the approximately 80 past and present members of the Hogness lab, as well as his colleagues from the Biochemistry Department at Stanford. The memories shared at that meeting captured many aspects of a remarkable person and career not immediately apparent from the above recitation of scientific accomplishments. The breadth of his vision was noted by S. Artavanis-Tsakonas, who noted that one was free to address almost any scientific problem in the Hogness lab, so long as you did it well and did it passionately. A remarkable illustration of this characteristic was Hogness's support of one of his graduate students, J. Nathans, who cloned the bovine rhodopsin and human rhodopsin and opsin genes, discovering the molecular basis of red-green color blindness. The breadth of Hogness's interests were described by P. Berg, who noted that he could likely have had as brilliant a career as an architect as he did in science, having designed not only the home he built at Stanford, but also the layout of the laboratories in the Department of Biochemistry. One well-known trait was pointed out by A. Kornberg, who described Hogness's "passionate reluctance to publish." There is indeed a remarkable body of work never published, including the first differential cDNA screens and the discovery of the TATA box. However, as noted by many, this did not in most cases interfere with the subsequent careers of the lab members doing the work, perhaps reflecting the eloquence of their mentor in writing letters. In any case, the relationship between David Hogness and his lab members was perhaps best captured in a quote attributed to a former postdoc, who said "Every time I think of Hogness, my heart warms up."

David S. Hogness was born on November 17, 1925, in Oakland, California, and obtained his B.S. (1949) and Ph.D. (1952) degrees from the California Institute of Technology, where he did his thesis research with Professor Herschel Mitchell in both the Chemistry and Biology Divisions. After postdoctoral studies in Jacques Monod's laboratory at the Institut Pasteur, Paris (1952–1954), Hogness was appointed in 1955 to a faculty position in the Microbiology Department chaired by Arthur Kornberg at Washington University, St. Louis. In 1959, the entire department moved to Stanford University where they created a new Department of Biochemistry. He chaired this department from 1986 to 1989, when he joined the new Department of Developmental Biology that he had done much to create, becoming Professor of Developmental Biology and Biochemistry. In 1991 he was named the Rudy J. and Daphne Donohue Munzer Professor of Developmental Biology and Biochemistry. He was elected to membership in the National Academy of Science (1976), the American Academy of Arts and Sciences (1976), Honorary Membership in the Japanese Biochemical Society (1987), and Associate Membership of EMBO (1992). He has received several awards including the Genetics Society of America Medal (1984), the Newcomb Cleveland Prize of the American Association for the Advancement of Science (1966 and 1988), the Ricketts Award, University of Chicago (1977), the Humboldt Research Award, Germany (1995), the Darwin Prize, University of Edinburgh (1995), the March of Dimes Prize in Developmental Biology (1997, shared with W. Gehring), and the Lifetime Achievement Award of the Society for Developmental Biology (2002). Hogness has been awarded honorary degrees by the University of Crete, Greece, and the University of Basel, Switzerland (both in 1986).

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