Scientific Report 2005

Molecular Biology

Chairman’s Overview

Research in the Department of Molecular Biology encompasses a broad range of disciplines, extending from structural and computational biology at one extreme to molecular genetics at the other. During the past year, our scientists continued to make rapid progress toward understanding the fundamental molecular events that underlie the processes of life. Major advances have been made in elucidating the structural biology of signal transduction and viral assembly, in understanding mechanisms of viral infectivity, in determining the structure of membrane proteins, in understanding the molecular basis of nucleic acid recognition and DNA repair, and in determining the mechanism of ribosome assembly. Progress was made in elucidating the molecular events involved in regulation of the cell cycle, in tumor development, in induction of sleep, in the molecular origins of neuronal development and of CNS disorders, in the regulation of transcription, and in the decoding of genetic information in translation. Finally, new advances were made in the design of novel low molecular weight compounds that can specifically regulate genes and in the area of biomolecular engineering, building novel functions into viruses, antibodies, zinc finger proteins, RNA, and DNA. Progress in these and other areas is described in detail on the following pages, and only a few highlights are mentioned here.

Structural biology continues to be a major activity in the department, and many new x-ray and nuclear magnetic resonance structures of major biomedical importance were completed during the past year. Among the highlights was the determination, in Ian Wilson’s laboratory, of the first structure of a human Toll-like receptor, a protein that plays a key role in the innate immune system as a sensor of molecules associated with the cell wall and genetic material of pathogenic bacteria. Dr. Wilson and his coworkers also reported structures of the protein CD1a, another key receptor in the innate immune response, and of an antibody that neutralizes most strains of HIV. Other advances came in the area of membrane protein crystallography: Geoffrey Chang and colleagues determined the structures of 2 proteins (MsbA and EmrE) involved in drug transport and the development of drug resistance in bacteria and cancer cells, and David Stout and James Fee determined the structure of a cytochrome ba₃ oxidase. Finally, the Joint Center for Structural Genomics, directed by Ian Wilson, was selected by the National Institutes of Health as 1 of 4 large-scale centers for high-throughput determination of protein structures.

Several research groups are working in areas directly related to drug discovery and protein therapeutics. Joel Gottesfeld and colleagues have developed a small DNA-binding molecule that turns off the gene for histone H4 and blocks replication in a wide variety of cancer cells. The compound is active in vivo and blocks the growth of tumors in mice. Research in the laboratory of Carlos Barbas is directed toward genetic reprogramming of tumor cells via engineered zinc finger transcription factors. These artificial transcription factors are powerful tools for determining the function of genes in tumor growth and progression and have potential applications in cancer therapy. John Elder and colleagues are studying development of resistance to drugs that target the HIV protease. A complementary approach to the same problem is being taken by Arthur Olson and researchers in his laboratory in their FightAIDS@Home program. This program is a large-scale computational effort in which a grid of personal computers distributed around the world is used to design effective therapeutic agents that target the HIV protease. Raymond Stevens and coworkers have engineered a phenylalanine ammonia lyase enzyme as a potential injectable therapeutic agent for treating phenylketonuria. Finally, Paul Schimmel and colleagues have identified a naturally occurring fragment of tryptophanyl-tRNA synthetase that is highly potent in arresting angiogenesis and is being introduced in a clinical setting for treatment of macular degeneration.

Many of the research groups in the department are applying the tools of molecular genetics to understand the molecular basis of human disease. Jerold Chun and his colleagues recently established a relationship between lysophospholipid signaling and neuropathic pain. In addition, they made the surprising discovery that lysophosphatidic acid receptors play an important role in embryonic implantation and thereby influence female fertility. Research in the laboratory of Luis de Lecea has indicated that a newly discovered neuropeptide, neuropeptide S, plays a functional role in modulation of sleep and suppression of anxiety. Work in the laboratory of James Paulson has led to the development of novel microarray technology for profiling glycoproteins, a technology that could eventually be developed into a powerful diagnostic screen for various infections and diseases.

On the more fundamental side, major advances have been made in understanding mechanisms of protein and RNA folding, both in vitro and in a cellular environment. Research in the laboratory of Martha Fedor has resulted in new insights into mechanisms by which RNA folds into its specific functional structures and has provided evidence that RNA chaperones mediate folding pathways in the cell. Work by James Williamson and colleagues has led to a detailed map of the assembly landscape of the 30S ribosome, providing new understanding of the mechanism by which assembly proceeds through a succession of RNA conformational changes and protein binding events. Arthur Horwich and coworkers have made major progress in elucidating the mechanism by which the chaperone ClpA mediates unfolding and translocation of proteins.

Molecular biology remains a field of enormous opportunity and excitement. The scientists in the department are taking full advantage of powerful new technologies to advance our understanding of fundamental biological processes at the molecular level. Their discoveries will ultimately be translated into new advances in biotechnology and in medicine.