Robert L. Baldwin, D.Phil., Oxford, 1954. Professor of Biochemistry Emeritus. Experimental analysis of the mechanism of protein folding. The long-range goal is to understand how the instructions for folding are encoded in the amino acid sequence. One approach is to characterize the structures of folding intermediates and identify the structurally important interactions at each stage in the folding pathway. NMR and hydrogen exchange are the basic methods used. Another approach is to analyze the folding of small fragments of a protein. Currently under study is alpha-helix formation by chemically synthesized peptides of de novo design.

Paul Berg, Ph.D., Western Reserve, 1952. Cahill Professor in Cancer Research Emeritus, Department of Biochemistry. The genome and its expression; genetic recombination in eukaryotes: Mitotic recombination as one means for repairing deletions, insertions, and doublestrand breaks in DNA.

Patrick O. Brown, Ph.D., 1980, M.D., 1982, Chicago. Associate Professor of Biochemistry. Retroviral replication: To multiply, a retrovirus needs to insert a copy of its genome into the host cell chromosome. Genetic and biochemical approaches are used to investigate the mechanism and regulation of this process. Genomic analysis: Novel methods for mapping and characterizing genes in complex genomes are being developed and applied.

Douglas L. Brutlag, Ph.D., Stanford, 1972. Professor of Biochemistry. Application of information science to DNA/protein sequences and structures in order to understand the flow of information from genome to phenotype. Of particular importance is the problem of predicting structure and function from sequence. Critical methods used include machine learning, simulation, information theory, and statistics.

Gilbert Chu, Ph.D., M.I.T., 1973; M.D., Harvard, 1980. Associate Professor of Medicine (Oncology); Associate Professor of Biochemistry. DNA repair, cancer biology, and immunology: Cells must recognize and respond to DNA damage in order to survive and maintain genomic integrity. Two classes of proteins are studied: those that bind and target bulky DNA adducts for nucleotide excision repair and those that bind to DNA ends for doublestrand break repair as well as for V(D)J recombination, a process that generates immunological diversity. In addition to these biochemical pathways, implications for genetic diseases, carcinogenesis, and cancer treatment are being studied.

Ronald W. Davis, Ph.D., Caltech, 1970. Professor of Biochemistry and Genetics; Director, Stanford DNA Sequencing and Technology Center. Whole genome DNA sequence and functional analysis: The DNA sequence of the genome of Saccharomyces cerevisiae has been completed. Using the sequence, new technology is being developed to rapidly analyze the functions of the open reading frames by deletion analysis, gene expression level, gene fusion, and protein product. New technology called "quantitative phenotypic analysis," using DNA chips and a molecular bar coding technique, has been developed and will allow massively parallel analysis. In a separate approach, oligonucleotides for whole genomes are synthesized by our collaborators at Affymetrix. . The genes are analyzed for expression level under a wide range of growth conditions: cell cycle control, meiosis, DNA replication initiation and propagation mapping. These genes will also be used for a functional analysis program. The DNA chips are also being used to genetically map multigenic traits. New programs in drug discovery and molecular ecology are being initiated. Similar developments are being applied to the higher plant Arabidopsis. We have developed new technology (DHPLC) to rapidly identify sequence variation in Arabidopsis and Human and which is being applied at the whole genome level.

Pehr. A. B. Harbury, Ph.D., Harvard, 1994. Assistant Professor of Biochemistry. Structural determinants of protein folding, design and small molecule recognition. We are studying the molecular mechanisms that confer specific shapes on proteins, and which determine how proteins recognize small molecules. The goal is to elucidate predictive principles by which novel structures and catalytic properties can be conferred accurately on designed polypeptides, and to achieve the rational design of ligands for proteins of known conformation. The lab relies primarily on three tools: (a) the computational engineering of structures at atomic resolution, made possible by the advent of classical molecular mechanics potentials (b) biophysical characterization of peptide proteins composed from an expanded amino acid alphabet (c) the generation and screening of combinatorial libraries, both in vivo using bacterial screens and sexual PCR and in vitro by synthesis of compounds on solid support.

Daniel Herschlag, Ph.D., Brandeis, 1988. Associate Professor of Biochemistry. Mechanisms of catalysis by RNA and proteins: The general goal of the research is to understand how RNA and protein enzymes achieve their enormous rate enhancements and exquisite specificity, and the general strategy is to compare mechanistic features of RNA and protein enzymes, both naturally occurring and selected via combinatorial approaches. The differences help reveal properties of RNA and proteins as macromolecules; the similarities help reveal the chemical and physical principles of biological catalysts. Further, these same chemical and physical principles more generally delineate the capabilities and limitations of biological systems. Correspondingly, mechanistic approaches are being exploited to understand more complex biological processes. Additional areas of investigation include, most notably, eukaryotic translation initiation, catalysis of phosphoryl transfer by RNA and protein enzymes, model studies of phosphoryl transfer and hydrogen bond energetics, RNA folding, RNA/protein interactions, and enzymes that manipulate RNA and DNA. Here we are combining mechanistic approaches with the power of DNA arrays to simultaneously assay the distribution of all mRMAs in yeast.

David S. Hogness, Ph.D., Caltech, 1952. Professor of Developmental Biology and Biochemistry. Molecular genetics and biochemical analyses of Drosophila development: genetic regulatory hierarchies (networks) controlling the larva-to-fly metamorphosis and their activation by the steroid hormone ecdysone via its nuclear receptor. Current focus is on (i) mechanisms for ecdysone receptor activation via heterodimorization and chaperone catalysis, (ii) the genes that provide a temporal linkage between the genetic networks activated by adjacent pulses of ecdysone, and (iii) the role of ecdysone-induced cyclin-activated kinases in metamorphosis.

Dale Kaiser, Ph.D., Caltech, 1955. Professor of Biochemistry and Developmental Biology. Regulation of multicellular development: How do cells in an embryo coordinate their activities so that the right cell is in the right place at the right time? Myxobacteria are perhaps the simplest organisms that exhibit multicellular development with cellular differentiation. They permit both biochemical and genetic studies of cellcell interactions necessary for development and differentiation. Two extracellular factors needed at different times for transcription of developmentally regulated genes have been purified. The route by which these factors alter transcription is being examined.

Arthur Kornberg, M.D., Rochester, 1941. Merner Professor of Medical Science, Department of Biochemistry. Inorganic polyphosphate (poly P) is a linear polymer of many tens or hundreds of orthophosphate (Pi) residues linked by high energy, phosphoanhydride bonds. Likely a prominent precursor in prebiotic evolution, poly P is now found in every living thing: bacteria, fungi, protozoa, plants, and mammals. Our mission is to understand the biochemistry, genetics and physiology of this "forgotten" polymer. We have found poly P to be essential in E. coli for responses to stress and survival and likely needed for the virulence of the major pathogens. Current studies explore the molecular basis for each of the many functions of poly P.

Mark A. Krasnow, Ph.D., 1983, M.D., 1985, Chicago. Associate Professor of Biochemistry. Genetic, cellular, and biochemical analysis of epithelial morphogenesis, using the Drosophila tracheal (respiratory) system and mouse lung as models. The goals are to understand the molecular basis of how cells migrate and find their targets, how the migrating cells assemble into tubes, and how the tubes interconnect.

I. Robert Lehman, Ph.D., Johns Hopkins, 1954. Hume Professor in the School of Medicine, Department of Biochemistry. DNA replication in eukaryotes: The replication of the Herpes simplex type 1 (HSV-1 ) DNA as a model eukaryotic chromosome with a well-defined origin of replication is being examined. The lab has purified the seven Herpes-encoded gene products that are both necessary and sufficient for HSV-1 DNA replication. They are a DNA polymerase with its processivity-enhancing subunit, a single-stranded DNA-binding protein, a heterotrimeric helicase-primase and an origin-binding protein that very likely serves to initiate DNA replication. Current efforts are aimed at reconstituting origin-dependent HSV-1 DNA replication with these purified proteins, supplemented with as yet undefined host factors.

Suzanne R. Pfeffer, Ph.D., U.C. California, San Francisco, 1983. Professor and Chairman of Biochemistry. Biochemistry of intracellular transport: Research is aimed at the molecular mechanisms of protein targeting to distinct intracellular compartments. Protein transport between endosomes and the Golgi apparatus is studied in a cellfree system to discover proteins that catalyze vesicular transport. The Raslike GTPase, Rab9, and a Rabspecific, nucleotide exchanger are required. Also being investigated is how Golgi complexes are distributed to daughter cells after mitosis.

James A. Spudich, Ph.D., Stanford, 1968. Professor of Biochemistry; Professor of Developmental Biology. Biochemical, molecular genetic, and structural studies of actin, myosin, and associated regulatory proteins from eukaryotic cells: Work focuses on the design and development of in vitro assays for ATPdependent movement of purified myosin on filaments reconstituted from purified actin. Myosin gene cloning and expression of sitedirected mutagenized forms, which are analyzed for altered functions is also carried out. Emphasis is on the molecular basis of energy transduction that leads to myosin movements on actin filaments and on regulation of actin and myosin interactions and of their assembly states, with particular interest in Dictyostelium chemotaxis, cytokinesis, and other forms of cell movement.

Julie Theriot, Ph. D., U.C. San Francisco, 1993, Assistant Professor of Biochemistry. Cell biology of host-pathogen interactions. We study the interactions between infectious bacteria and the human host cell actin cytoskeleton. Listeria monocytogenes and Shigella flexneri are unrelated food-borne bacterial pathogens that share a common mechanism of invasion and actin-dependent intercellular spread in epithelial cells. Our studies fall into three broad areas: the biochemical basis of actin-based motility by these bacteria, the biophysical mechanism of force generation, and the evolutionary origin of pathogenesis.