2001 GSA Honors and Awards

The 2001 Genetics Society of America Medal

THE 2001 GSA Medal is given to H. Robert Horvitz to honor his many contributions to genetics research and training. One of the pioneers in the Caenorhabditis elegans system, Bob has cut a genetic swath through many areas of developmental biology, cell biology, and neurobiology, discovering new gene families and defining genetic pathways. Along the way Bob has trained many of the current leaders in the C. elegans field. This award specifically recognizes Bob's accomplishments during the past 15 years in two important areas: the analysis of vulval development and function, and the elucidation of the pathway controlling programmed cell death.

After undergraduate studies at the Massachusetts Institute of Technology, Bob pursued graduate studies at Harvard University with James Watson and Walter Gilbert on the regulation of Escherichia coli RNA polymerase by bacteriophage T4. He then joined Sydney Brenner at the MRC Lab of Molecular Biology in 1974 to learn the then-new C. elegans system. While there, he developed interests in two processes that have driven much of the work in his lab: programmed cell death and vulval development and function. He had planned to study muscle development, and upon arrival he joined forces with John Sulston in an ambitious project to determine postembryonic cell lineages. The programmed cell deaths that occurred in the lineage kindled an interest that Bob would return to after his postdoc studies. In a pioneering study, Horvitz and Sulston applied genetics to the complex problem of understanding how the cell lineage was specified. They tried a variety of screens and found a fascinating set of cell lineage mutations that they reported in a 1980 GENETICS article. Bob realized that one class of mutants that emerged in the screens, egg-laying defective mutants—visualized by their "bag-of-worms" phenotype—would provide an entry point to several aspects of development and behavior. The "bags of worms" arose either from failure of development of the vulva, the epidermal egg-laying apparatus, or from failure in development or function of muscles and nerves required for egg laying. After moving to MIT in 1977, Bob recruited a group of talented students and postdocs to help him saturate the genetic map for mutations affecting vulval development and egg laying. These genetic studies set the groundwork for defining pathways of developmental control, as well as many aspects of neuronal development and function.

Bob's genetic studies on the development of the egg-laying system have had a major impact in developmental biology. The analysis of the vulva defective mutations led to what is arguably the most complete understanding of a developmental induction and contributed significantly to the elucidation of the conserved EGF-receptor/RAS signaling pathway for fate specification. As an example, consider the first three of the cell lineage genes found. lin-1 encodes an ETS domain protein at the nuclear end of the RAS pathway, lin-2 is necessary for EGF-receptor localization, and lin-3 encodes the EGF-like vulval inductive signal. In addition, Bob's studies of egg-laying mutants that affected sex muscle precursor development identified the C. elegans FGF-receptor and, in 1992, sem-5, the key missing link in the signaling pathway from transmembrane "receptor" tyrosine kinases to RAS activation. The key result was based on the placement of sem-5 upstream of RAS in a genetic pathway. Following up on an elegant bit of genetic sleuthing Bob reported in the 1980 cell lineage paper, in 1989 he and student Edwin "Chip" Ferguson defined two apparently redundant pathways involving the "synthetic multivulva" genes. When worms are defective in any of the "A" class of genes as well as in any of the "B" class of genes, they display a "multivulva" phenotype. While these two pathways remain a fascinating genetic puzzle after a decade, Bob has found that some of these genes in the B pathway encode Rb pathway proteins, putting a molecular face on one of the two pathways.

Many of the genes identified in the egg-laying screens defined new gene families involved in a host of biological phenomena, after they were positionally cloned in Bob's lab or in the labs of his students. The vulval lineage gene lin-11 is the L in the LIM homeodomain family. The cell lineage regulator unc-86 is the U in POU domain transcriptional regulators. lin-12 is a founding member of the Notch family of receptors. lin-4, necessary for developmental timing, encodes the first of the recently expanded families of micro-RNAs. egl-10, a regulator of egg-laying behavior, was a founding member of the RGS family of regulators of G protein signaling.

At the same time that Bob was collecting and analyzing the egg-laying defective mutations, he began his study of the poorly understood developmental phenomenon of programmed cell death or apoptosis. His genetic studies led to the identification of the core players in the canonical pathway that controls apoptosis. In a clever screen published in 1986, Hilary Ellis and Bob discovered ced-3 and ced-4 as genes required for most apoptosis in C. elegans. These genes defined the beginning of a cell death pathway. Additional screens for cell death genes filled out the pathway. Analysis of mutations identified in screens for worms with persistent cell corpses defined about 10 genes involved in the phagocytosis of the apoptotic cells. Continuing screens for mutations that block cell death identified a dominant mutation in ced-9. Reversion of the dominant mutation and epistasis analysis led to the understanding that ced-9 protects against cell death by antagonizing the action of ced-3 and ced-4. The cloning of ced-9 revealed that it was homologous to the mammalian cell death gene bcl-2. This discovery was a major advance in the cell death field because it linked genetic pathway analysis in C. elegans to biochemical and oncogenetic studies in human and mouse. This advance rapidly led to the discovery of caspases (i.e., ced-3) and an explosion in the apoptosis field because the results from C. elegans led directly to new discoveries in mammalian systems. Bob's screens of egg-laying mutants also contributed to the cell death analysis. A dominant mutation in egl-1 proved to result from an inappropriate programmed cell death of neurons that innervate the vulval muscles and was subsequently found to be required for all cell deaths. Indeed, this phenotype of egl-1 mutants allowed screening for mutants defective in cell death pathways genes such as ced-9.

Bob also has had a longstanding interest in inherited human diseases, especially Huntington's disease and amyotrophic lateral sclerosis. He has been a major advisor to the Hereditary Disease Foundation and the ALS Association. Bob was a major player in the collaborative cloning of the first ALS gene and in a series of related molecular and genetic studies.

Bob's contributions to training in genetics are as impressive as his research accomplishments. Bob set standards of genetic rigor through his papers, through his reviewing of the work of others, and through the training of students and postdocs in his lab. Thirty of his former students and postdocs now have their own C. elegans laboratories. The experimental approach, scientific rigor, and rapid progress in the labs of these former students and postdocs show Bob's influence. Projects in Bob's lab started with genetic screens followed by intensive definition of loss-of-function phenotypes and construction of many double mutants to infer pathway relationships. When coupled with positional cloning, these studies were key contributors to the paradigm of developmental genetics that has led to our understanding of how genes control development and is beginning to make inroads into how genes control behavior.

Bob is not only a pioneer in the use of the C. elegans system but has also been a leader and a spokesperson for the C. elegans and broader biomedical research communities. He was an organizer of three of the first six International C. elegans Meetings and has been a shaper of policy and practices within the community. He served as president of the Genetics Society of America and on their Board of Directors. Bob has been active in NIH Genome Council and helped pave the way for the extraordinary effort of the C. elegans Sequencing Consortium to deliver the first complete sequence of a metazoan. He has had a strong interest in public science policy, serving on the Joint Steering Committee for Public Policy and the American Society for Cell Biology Public Policy Committee, among other efforts. Bob has been a major advocate and cheerleader for C. elegans in particular and the power of developmental genetics in general through his seminars and talks at national and international meetings. He was a strong advocate for National Cancer Institute funding of model organisms such as yeast, worms, and flies as co-chair of the NCI Working Group on Preclinical Models for Cancer. Bob's most important statements, however, have been the amazing series of discoveries made in his laboratory that demonstrate how genetic analysis in a model organism help solve biological problems such as the mechanism of programmed cell death.

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