Our Distinguished Faculty

There are two common characteristics of all of the faculty in the Genetics Program. First, all of these individuals have vigorous research programs that involve some aspect of Genetics. Second, all of the faculty are actively interested in training the next generation of geneticists. There are nearly 100 Genetics Program faculty, with research interests reflecting the interdisciplinary nature of the program. These are categorized into broad areas of investigation including: Cancer Biology; Cell cycle, DNA replication, recombination, and repair; Development; Eukaryotic Cell Biology and Cell Signaling; Genomics, Computational and Structural Biology; Human Genetics and Gene Therapy; Microbial Pathogenesis and Gene Therapy; Neurobiology and Behavior; Plant Biology; Population Genetics and Evolution; and Regulation of Gene Expression. This diversity gives students a wide range of research opportunities

Cancer Biology
Dafna Bar-Sagi, Wen-Tien Chen, Howard Crawford, Greg Hannon, Michael Hayman, Yuri Lazebnik, Christopher Lee, Scott Lowe, Kenneth Marcu, Ute Moll, Sentil Muthuswamy, Scott Powers, Linda VanAelst, Michael Wigler, Wei-Xing Zong.

Cell Cycle, DNA Replication, Recombination, and Repair
Dan Bogenhagen, Paul Fisher, A. Bruce Futcher, Arther Grollman, Nancy Hollingsworth, Janet Leatherwood, Arne Stenlund, Bruce Stillman.

Development
Michael Frohman, J. Peter Gergen, Michael Hadjiargyrou, Jen-Chih Hsieh, Bernadette Holdener, Alea Mills, Howard Sirotkin, Ken-Ichi Takemaru, Gerald Thomsen, Styliana Tsirka.

Eukaryotic Cell Biology and Cell Signaling
Carl Anderson, Debbie Brown, Nicholas Carpino, Neta Dean, Dale Deutsch, Berhane Ghebrehiwet, Tatsuya Hirano, James Konopka, William Lennarz, Craig Malbon, Aaron Neiman, Joav Prives, Clint Rubin, David Spector, William Tansey, Thomas White.

Genomics, Computational and Structural Biology
Dax Fu, Leemor Joshua-Tor, Richard McCombie, Vivek Mittal, Andy Neuwald, John Reinitz, Steve Skiena, Steven O. Smith, Michael Zhang.

Human Genetics and Gene Therapy
Wadie Bahou, J. Craig Cohen, Paul Freimuth, Eli Hatchwell, Patrick Hearing, Nancy Mendell, Jonathan Sebat.

Microbial Pathogenesis and Gene Therapy
Jorge Benach, James Bliska, Carol Carter, Martha Furie, Erich Mackow, Jacek Skowronski, David Thanassi, Eckard Wimmer.

Neurobiology and Behavior
Turhan Canli, Holly Colognato, Hollis Cline, Joshua Dubnau, Grigori Enikolopov, Z. Josh Huang, Maurice Kernan, Roberto Malinow, Mirjana Maletic-Savatic, Styliani-Anna Tsirka, Timothy Tully, Yi Zhong.

Plant Biology
Vitaly Citovsky, David Jackson, Wolfgang Lukowitz, Robert Martienssen, Marja Timmermans.

Population Genetics and Evolution
Michael Bell, Geeta Bharathan, Walter Eanes, John True.

Regulation of Gene Expression
Paul Bingham, John Dunn, Wali Karzai, Adrian Krainer, Nancy Reich, Rolf Sternglanz, F. William Studier.

Selected biographies follow:

CARL W. ANDERSON, Senior Geneticist and Chair
Ph.D. 1970, Washington University
Biology Department, Brookhaven National Laboratory
Carl W. Anderson is a member of the American Association for the Advancement of Science, the American Society for Microbiology, the American Society for Virology, and is a founding organizer of the International Association for Protein Structure Analysis and Proteomics. His research centers on the cellular responses to DNA damage in mammalian cells. He has discovered and has characterized the DNA-activated protein kinase, DNA-PK, a very large protein kinase that regulates the non-homologous end-joining (NHEJ) pathway of DNA double-strand break repair. Anderson is also characterizing the role of post-translational modifications (phosphorylations and acetylations) to the human p53 tumor suppressor protein in response to genotoxic stress and has been instrumental in developing immunological reagents for detecting specific post-translational modifications. Anderson is interested in the molecular biology of human adenoviruses and has studied adenovirus entry and gene expression in productive and non-productive infections and the role of the adenovirus proteinase in adenovirus assembly.
(631) 344-3375, cwa@bnl.gov

WADIE BAHOU, Associate Professor
Ph.D. 1980, University of Massachusetts
Chief, Division of Hematology, Department of Medicine
Wadie F. Bahou is interested in the genetics of human hemostatic/thrombotic proteins, focusing on platelet and endothelial cell biology. His immediate research interests include genetic approaches for hemophilia (factor VIII deficiency) using novel viral and liposomal delivery approaches and the genetics of hypercoagulability. In addition to factor VIII, the laboratory is studying the emerging class of G protein-coupled protease receptors, particularly in delineating genetic abnormalities of these receptors that are causally involved in human diseases. Bahou and his lab engage in research involving genetic mapping and identification of novel disease-causing genes using a variety of state-of-the art approaches. Bahou is an established investigator of the American Heart Association and is a member of the NIH/NHLBI Hematology-2 Study Section on Business/Technology Innovative Grants (SBIR/STTR).
(631) 444-2059, wadie.bahou@sunysb.edu

DAFNA BAR-SAGI, Professor
Ph.D. 1984, University at Stony Brook
Department of Molecular Genetics and Microbiology
Dafna Bar-Sagi is interested in the control of normal cell growth by extracellular signals and how this control is disrupted in cancer cells. Her research focuses on the Ras signaling pathway, which plays a critical role in the transduction of growth-promoting signals from the cell surface to the nucleus. This pathway is frequently deregulated in the wide variety of human cancers. Bar-Sagi’s research group is employing biochemical and cell biological approaches to define the mechanisms by which normal cells are converted to cancer cells due to excessive Ras signaling. The overall goal of her research is to identify signaling events that can be targeted for anti-cancer therapies.
(631) 632-8811, barsagi@pharm.som.sunysb.edu

MICHAEL BELL, Associate Professor
Ph.D. 1976, University of California at Los Angeles
Department of Ecology and Evolution
Michael Bell’s research is concerned with explaining patterns of morphological variation in time and space, and employs a “multidimensional analysis” that incorporates genetics, development, selection mechanisms, paleontology, and systematics. By placing geographical variation in a phylogenetic context, it becomes possible to identify recurrent trends in evolution and to assess the relative importance of constraints that are imposed by the environment and those that are intrinsic properties of the organism. For example, the three-spine stickleback, Gasterosteus aculeatus, has been seen in freshwater environments many times. Populations that have invaded freshwater independently often exhibit similar phenotypic properties that are absent from their common marine ancestor. Thus, one can be confident that the cause of these phenotypic similarities is not their presence in the common ancestor, but their independent evolution under common environmental conditions or intrinsic constraints.
(631) 632-8574, mabell@life.bio.sunysb.edu

JORGE BENACH, Professor and Director, Center for Infectious Diseases
Ph.D. 1972, Rutgers University
Department of Molecular Genetics and Microbiology
Jorge Benach’s research focuses on the pathogenesis of spirochetal infections and their host responses, particularly how it is manifested in Lyme disease and Rocky Mountain spotted fever.
Benach was a 1992 Fulbright-Hays Fellow and Exchange Professor.
(631) 444-3520, jbenach@path.som.sunysb.edu

GEETA BHARATHAN, Assistant Professor
Ph.D. 1993, University of Arizona
Department of Ecology and Evolution
Geeta Bharathan examines the systematic patterns of variation in developmental characters in order to research the interplay between development and evolution in plants. She does this using a two-pronged approach: phylogenetic analyses to assess evolutionary relationships among taxonomic groups, and analyses of characters within the phylogenetic framework to uncover systematic patterns of variation. The taxonomic scope of Bharathan's work has centered on the angiosperms, in general, and the monocotyledons, in particular. Phylogenetic studies of relationships among major monocot lineages have involved analyses of molecular and morphological data; Bharathan studies developmental and evolutionary patterns of variation in characters at different levels. Her future work will involve studies of phylogenetic relationships and character evolution in the Dioscoreales, a tropical monocot group. This group may be pivotal for the study of the evolution of several distinctive characters of monocots.
(631) 632-9508, geeta@life.bio.sunysb.edu

PAUL BINGHAM, Associate Professor
Ph.D. 1979, Harvard University
Department of Biochemistry and Cell Biology
Paul Bingham’s primary interest is in gene regulation and the effects of transposable evidence in gene expression. He has worked mainly on the white locus of Drosophila melanogaster, which has a system whose gene regulation is very well understood. He is also interested in how patterns of gene regulation might influence molecular evolution and speciation. Bingham’s work includes the analysis of behavior and properties of germ line genomic parasite transposons. He is studying several cases in Drosophila in which transposon mediated rearrangements of the genomic sequences of cellular hosts create novel combinations of structural and regulatory genetic elements with surprising, informative properties.
(631) 632-8542, bingham@life.bio.sunysb.edu

JAMES BLISKA, Associate Professor
Ph.D. 1987, University of California at Berkeley
Department of Molecular Genetics and Microbiology
James Bliska’s research focuses on how pathogenic bacteria interfere with signal transduction pathways in human cells. His lab utilizes a combination of genetic and molecular approaches to investigate bacterial-host cell interactions. Of particular interest is a specialized type III protein secretion system found in a variety of pathogenic bacteria that functions to inject effector molecules directly into human cells. From the study of type III secretion systems and their role in bacterial pathogenesis, Bliska hopes that new strategies will be developed to prevent infections in the human population, as well as increase our understanding of the biology of human cells.
(631) 632-8782, jbliska@ms.cc.sunysb.edu

DANIEL BOGENHAGEN, Professor
M.D. 1977, Stanford University
Department of Pharmacological Sciences, School of Medicine
Daniel Bogenhagen is interested in the molecular biology of mitochondria. Mitochondria play a vital role in cell survival by generating ATP, synthesizing heme, and coordinating lipid metabolism. Recent studies have also shown that mitochondria are intimately involved in cell death by apoptosis. The maintenance of mitochondria depends on expression of the mtDNA genome to provide a small number of gene products that are assembled into respiratory complexes along with other nuclearly encoded subunits imported into mitochondria. Thus, mitochondria provide an ideal opportunity to study the coordinate regulation of cell function at all genetic levels, from replication and repair to transcription and translation. The Bogenhagen laboratory is engaged in studies of many of the key proteins involved in maintenance of mtDNA. This laboratory has been among the first to purify and clone the heterodimeric DNA polymerase, RNA polymerase, two transcription factors, mtDNA ligase, and mitochondrial single-stranded DNA binding protein. These proteins are being used to reconstitute transcription and replication reactions in vitro. In addition, the Bogenhagen laboratory is beginning a broad-based effort to catalog and characterize all proteins involved in mtDNA maintenance using a proteomic approach.
(631) 444-3068, dan@pharm.sunysb.edu

Deborah A. Brown, Associate Professor
Ph.D. 1987, Stanford University
Department of Biochemistry and Cell Biology
Recent work has shown that lipids in biological membranes do not always mix uniformly. Instead, membranes contain microdomains that are enriched in certain lipids. Deborah Brown studies cholesterol- and sphingolipid-rich membrane domains called rafts. Rafts play important roles in cell-surface signal transduction, cell polarity, and protein sorting in the secretory and endocytic pathways. These functions result from the fact that certain proteins have a high affinity for the unique lipid environment found in rafts and are concentrated in the domains. Brown combines cell biological and biophysical approaches (the latter in collaboration with Erwin London) to study how lipids and proteins associate in rafts, how rafts are organized in cell membranes, and how they function. Some rafts are found in plasma membrane pits called caveolae. Caveolae are formed from homo-oligomers of an unusual membrane protein called caveolin, which has been implicated in integrin signaling and regulation of cell growth. Brown uses caveolin mutants to learn how caveolin interacts with rafts, and how this interaction is important in the function of caveolae.
(631) 632-8563, deborah.brown@sunysb.edu

CAROL A. CARTER, Professor
Ph.D. 1972, Yale University
Department of Molecular Genetics and Microbiology
The laboratory of Carol Carter focuses on the assembly of the Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immunodeficiency Syndrome (AIDS). Assembly of this virus is a multi-stage process that involves both viral and cellular proteins and takes place both in the cytoplasm and on the inner surface of the plasma membrane. The virus may use, transport, and export trafficking cellular machinery about which little is known. The potential of this stage of replication as a target for anti-viral drug design has not yet been exploited because the assembly process is not yet understood in molecular detail. Carter’s specific interests are elucidating the structure and function of the proteins involved and studying the required protein-membrane interactions. The goal of these studies is to identify critical events feasible for the design of anti-viral agents.
(631) 632-8801, ccarter@ms.cc.sunysb.edu

VITALY CITOVSKY, Associate Professor
Ph.D. 1987, Hebrew University, Jerusalem
Department of Biochemistry and Cell Biology
Vitaly Citovsky is a plant biologist who focuses on inter- and intracellular transport of nucleic acid-protein complexes. Specifically, Citovsky’s lab has two major ongoing projects. The first project studies how plant virus genomic RNA and DNA molecules are transported between cells through intercellular connections, the plasmodesmata (PD). The second project examines the mechanism of the nuclear import of Agrobacterium T-DNA. The first study involves plant intercellular communication, which largely occurs via cell-to-cell connections, the PD. As an experimental system to study PD transport and regulation, Citovsky is using cell-to-cell movement proteins of plant viruses that interact with PD to increase their size exclusion limit. Thus, these proteins are utilized as tools to identify their cellular receptors involved in PD transport. In addition, several mutants of Arabidopsis thaliana, a genetic model plant, have been isolated that are defective in viral cell-to-cell spread and, by implication, in PD transport. These mutants will be used to elucidate the molecular pathways for intercellular communication through PD.
(631) 632-9534, vitaly.citovsky@sunysb.edu

HOLLIS CLINE, Professor
Ph.D. 1985, University of California at Berkeley
Cold Spring Harbor Laboratory
Hollis Cline is a Professor at Cold Spring Harbor Laboratory. She obtained a Bachelor of Arts degree from Bryn Mawr College, Pennsylvania, and a Ph.D. in Neuroscience from the University of California at Berkeley in 1985. Cline received her post-doctoral training from Dr. Martha Constantine-Paton at Yale University, and from Dr. Richard Tsien at Stanford University. Cline’s research focuses on the growth of neurons in the brain and the development of synaptic connections between different brain regions. These questions are addressed in her lab using imaging techniques, genetic manipulation of particular proteins, and electrophysiology to measure the communication between neurons. Ongoing experiments test the function of known and novel genes in the development of neuronal structure and synaptic transmission. These studies contribute to the identification of activity-dependent biochemical pathways controlling developmental plasticity. Cline has been a recipient of several honors and awards including awards from the McKnight Fund, the Klingenstein Foundation, the Patterson Trust, the National Down’s Syndrome Society, the Eppley Foundation, and the Hoffritz Fund.
(631) 367-8816, cline@cshl.org

NETA DEAN, Associate Professor
Ph.D. 1988, University of California at Los Angeles
Department of Biochemistry and Cell Biology
Neta Dean’s research interests focus on the regulation of glycosylation and cell wall biogenesis in yeast. Glycosylation is an essential modification that functions in a variety of biological roles ranging from the stabilization of protein structure to the regulation of cell surface properties. Dean’s research aims to understand how this modification is regulated within the secretory pathway, how glycoproteins mediate their biological roles at the cell surface, and how cell wall biosynthesis is coordinated with growth and division. As a model system for most of these studies, the budding yeast S. cerevisiae is used. Since cell surface carbohydrates are among the primary virulence determinants of pathogenic fungi, a major effort is also underway to understand the regulation of cell surface glycoprotein synthesis in the most frequently isolated human fungal pathogen, Candida albicans.
(631) 632-9309, ndean@notes.cc.sunysb.edu

JOHN J. DUNN, Senior Microbiologist
Ph.D. 1970, Rutgers University
Biology Department, Brookhaven National Laboratory
A primary objective of John Dunn’s research is to determine the molecular roles that T7 RNA polymerase has in initiation of site-specific “rolling circle” replication of T7 DNA and in T7 packaging. Dunn’s aim is to identify all the viral and cellular components in the replication and processing complexes and to provide a detailed molecular description of their interactions. Part of his efforts involve using recombinant DNA techniques to exploit the obvious potential of T7’s genetic elements to elicit high level expression of foreign proteins in Escherichia coli. The Dunn lab is using the T7 system to overexpress the genes encoding the major outer membrane proteins of the Lyme disease spirochete Borrelia burgdorferi, which causes a multisystematic disorder that is endemic to Long Island. Overexpression of these gene products may be useful for diagnostic immunoassays and/or production of vaccines against Lyme disease.
(631) 344-3012, jdunn@bnl.gov

WALTER F. EANES, Professor and Chair
Ph.D. 1976, University at Stony Brook
Department of Ecology and Evolution
Walter Eanes is engaged in a wide-ranging research program on the population genetics of Drosophila. His major research is focused on using nucleotide sequence data from natural populations to draw inferences about the historical pattern and strength of natural selection acting on the Drosophila genome. He is also interested in the role of transposable elements in the evolution of gene regulation and the evolution of gamete recognition proteins in mussels.
(631) 632-8593, walter@life.bio.sunysb.edu

GRIGORI ENIKOLOPOV, Associate Professor
Ph.D. 1978, Institute of Molecular Biology, USSR Academy of Sciences, Moscow
Cold Spring Harbor Laboratory
Grigori Enikolopov is interested in how cells progress along their differentiation pathways and how this progress is linked to their activity. His efforts have been focused mainly on nitric oxide (NO), a multifunctional short-lived signaling molecule. NO has a wide range of effects in humans, from regulating blood pressure to modulating brain activity. Enikolopov’s lab has recently discovered that NO plays yet another crucial role: it tells the cells in a developing organism when to stop dividing and to acquire their final characteristics. It is possible to manipulate cell division during development by supplying a source of NO or by removing the source of NO. His lab has shown that NO performs similar functions during brain development in vertebrates, such that by changing the levels of NO it is possible to increase the size of the brains of the Xenopus tadpoles. These findings suggest that NO acts as an essential negative regulator of cell number during tissue differentiation and organism development.
(631) 367-8316, enik@cshl.org

PAUL I. FREIMUTH, Biochemist
Ph.D. 1986, Columbia University
Biology Department, Brookhaven National Laboratory
Research in Paul Freimuth’s laboratory focuses on the interaction of viruses with their host cells. In earlier studies, his lab showed that a protein component of the adenovirus capsid contains a sequence motif, RGD, which is recognized by integrin coreceptors on the host cell plasma membrane. Virus mutants that have lost the RGD motif are viable but their entry into cells by endocytosis is delayed substantially. The initial attachment of adenovirus to the cell surface is mediated by a different receptor, CAR, which also mediates attachment of a subset of coxsackie viruses. In recent studies, Freimuth and collaborators at BNL determined an X-ray crystal structure of the adenovirus CAR-binding component in complex with the extracellular domain of CAR. This structure revealed that interfacial water molecules play a key role in the binding mechanism. Current work includes determination of the antigenic fine structure of the adenovirus CAR-binding component and the impact of immunoselection on the specificity and affinity of receptor binding, structural analysis of CAR binding to the coxsackie virus, and analysis of the regulation of the CAR gene expression.
(631) 344-3350, freimuth@sun2.bnl.gov

MICHAEL A. FROHMAN, Associate Professor
M.D., Ph.D. 1985, University of Pennsylvania
Department of Pharmacological Sciences
Michael Frohman’s research centers on both developmental and signaling topics. The primary current set of projects involves cellular and developmental roles for the signaling enzyme Phospholipase D, which is proposed to regulate the movement of membrane vesicles at a variety of locations in cells and embryos. Under exploration in mammalian cells are roles the enzyme family may play in release and re-uptake of neurotransmitters, or in secretion and endocytosis in general. Roles for the enzyme family in early development in mammals (using knockout animals) and in Drosophila are also being pursued. In Drosophila, the role of the enzyme in the process of cellularization, the development of new plasma membranes around each nucleus, represents the key cellular event being examined.
(631) 444-3060; michael@pharm.sunysb.edu

BRUCE FUTCHER, Associate Professor
D. Phil. 1981, Oxford University, England
Department of Molecular Genetics and Microbiology
The main research interest in Bruce Futcher’s lab is the control of cell division. In particular, the lab works on commitment to division and on the mechanisms that coordinate cell division with cell size. These mechanisms depend on the cyclin-dependent protein kinase Cdc28 and its substrates, and so identifying new substrates is an important approach. Most studies use the yeast S. cerevisiae, but when possible, discoveries made in yeast are pursued in mammalian cells.
A second interest of Futcher’s is microarray technology. Microarrays have been used by the lab to identify all 800 yeast genes that oscillate as a function of the cell cycle. The transcriptional programs controlling these genes are now being worked out. Microarrays are also being used to address related questions, in yeast and elsewhere. Futcher’s lab is also intrigued by aging. The laboratory works on telomeres and telomerase, with an interest in the idea that telomere shortening may contribute to human aging. Other possible contributors to human aging are also being considered.
(631) 632-4715, bfutcher@ms.cc.sunysb.edu

J. PETER GERGEN, Professor and Director, Center for Developmental Genetics
Ph.D. 1982, Brandeis University
Department of Biochemistry and Cell Biology
Peter Gergen's research investigates the regulation of gene expression during embryonic development. A major focus of this research over the last several years has involved studies of the function of the Drosophila Runt protein, the founding member of the Runt domain family of transcriptional regulators. Members of this protein family have pivotal roles in pathways extending from pattern formation and sex determination in insects to the development of bone and blood in humans. The work in the Gergen laboratory takes advantage of the wealth of information on the genetics and cell biology of the early Drosophila embryo to investigate mechanisms of transcriptional activation and repression by Runt domain proteins. This work utilizes several approaches, including forward and reverse genetic studies on gene function in vivo, biochemical structure-function analysis of protein:protein and protein:DNA interactions, and biophysical studies aimed at determining the structure of this novel family of DNA-binding proteins. The integration of these interdisciplinary approaches should provide fundamental new insights into the mechanisms used to regulate gene transcription during animal development.
(631) 632-9030, pgergen@life.bio.sunysb.edu

ARTHUR P. GROLLMAN, Professor
M.D. 1959, Johns Hopkins University
Department of Pharmacological Sciences, School of Medicine
The Laboratory of Chemical Biology focuses on the biological consequences of DNA damage with particular reference to molecular mechanisms of DNA replication, mutagenesis, and DNA repair. Site-specific methods are used to explore the mutagenic potential of defined DNA lesions in mammalian cells. Shuttle plasmid vectors are used to establish the efficiency and fidelity of translesional synthesis. Reactions, catalyzed by DNA polymerases, permit mutational events to be studied in vitro. The three-dimensional structure of damaged DNA is used to correlate molecular structure and biological function. This multidisciplinary approach permits Grollman and his students to elucidate the molecular basis of mutagenic specificity. Oxidative DNA damage is a major contributor to spontaneous mutagenesis, carcinogenesis, and the aging process. Grollman’s lab has determined the miscoding effects of DNA damage produced by reactive oxygen species and has defined an error-avoidance pathway that protects cells against mutations produced by 8-oxoguanine. DNA N-glycosylases and AP-lyases are central to this process. Genes for these enzymes have been cloned and the lab uses gene knockout technology to analyze effects of repair of oxidatively damaged DNA in transgenic mice.
(631) 444-3080, apg@pharm.sunysb.edu

MICHAEL HADJIARGYROU, Assistant Professor
Ph.D. 1992, City University of New York
Department of Bioengineering
Michael Hadjiargyrou studies the effects of biophysical stimuli on gene expression in skeletal tissue. Biophysical stimuli have been shown to accelerate fracture healing, increase bone density, alter mechanical strength, and affect the bone remodeling process. Although these are well-documented studies, they focus mainly on the tissue and cell level. Thus Hadjiargyrou and his team focus on the effects of biophysical stimuli on gene expression in the skeletal system in the context of fracture healing and osteopenia. Hadjiargyrou hypothesizes that finding novel genes during fracture repair and osteopenia might facilitate our understanding of these processes as well as to identify ideal gene candidates for biological intervention in wound repair and in the regulation of bone mass. To begin searching for such genes expressed during fracture healing and osteopenia, Hadjiargyrou’s group decided to take a molecular approach, utilizing the most recent advances in recombinant DNA technology.
(631) 632-1480, michael.hadjiargyrou@sunysb.edu

GREGORY HANNON, Associate Professor
Ph.D. 1992, Case Western Reserve University
Cold Spring Harbor Laboratory
A defining characteristic of a cancer cell is its ability to proliferate under circumstances that would prevent the growth of its normal counterpart. Gregory Hannon’s principal interest is the elucidation of pathways that underlie neoplastic transformation. Toward this end, he and his laboratory have developed a set of tools that allow the use of direct, functional approaches for the isolation of genes related to transformation in cultured cells. Specifically, Hannon’s laboratory investigates aspects of cellular mortality control/telomerase regulation, genome stability, and the role of myc in human tumor formation. Prompted by the need for a facile loss-of-function method for mammalian cells, Hannon has recently begun studying RNA interference—a process in which the introduction of dsRNA into C. elegans, Drosphophila, or plants results in a specific and heritable ablation of genes homologous to the dsRNA. Hannon has developed an in vitro system from cultured Drosophila cells that may allow the biochemical mechanism of this phenomenon to be elucidated.
(631) 367-8455, hannon@cshl.org

MICHAEL J. HAYMAN, Professor and Chair
Ph.D. 1973, National Institute of Medical Research, London, England
Department of Molecular Genetics and Microbiology
Michael Hayman’s research focuses on the mechanisms by which growth factor receptor functions to controlling growth, differentiation, and malignant disease and also on how oncogenes can cooperate to cause cancer.
Over the past several years, it has become apparent that growth factor receptors can function as oncogenes and play a causal role in cell transformation and oncogenesis. For example, analysis of human tumors derived from squamous epithelium has shown that the epidermal growth factor receptor (EGFR) is overexpressed in the receptor, and in chickens mutated forms of the EGFR are frequently transduced into avian retroviruses, giving rise to erythroid leukemias and sarcomas. Hayman’s laboratory is studying the signal transduction pathways activated by the growth factor receptors that are important in these pathogenic states. To understand these processes, the interactions between signaling pathways have to be studied. The model system under analysis studies leukemic cells that are induced to grow by signals from both the nuclear oncogene v-Ski and the oncogenic tyrosine kinase v-Sea. This system allows an analysis of the interaction between nuclear signals and signals from tyrosine kinases in leukemogenesis.
(631) 632 8792, mhayman@ms.cc.sunysb.edu

 

PATRICK HEARING, Professor
Ph.D. 1980, Northwestern University
Department of Molecular Genetics and Microbiology
Patrick Hearing studies the human DNA virus, adenovirus (Ad), as a model system of eukaryotic transcriptional regulation and control of cellular proliferation. Ad gene products regulate the E2F family of transcription factors, which are key players in cell cycle progression. How individual Ad proteins modulate the E2F pathway, and thereby regulate cellular proliferation, is being investigated. Other studies focus on Ad regulation of transcription by nuclear reorganization. The Hearing lab also is developing adenovirus as a vector for use in human gene therapy. This virus infects a variety of human cell types and establishes efficient expression of introduced genes. The broad objective of the research is to develop novel Ad vectors and approaches to produce these vectors. As part of these studies, he analyzes the sequences in Ad genome that direct the packaging of viral DNA into capsids. Research focuses on the DNA sequences that direct viral DNA packaging and proteins that interact with these elements.
(631) 632-8813, phearing@ms.cc.sunysb.edu

TATSUYA HIRANO, Associate Professor
Ph.D. 1989, Kyoto University
Cold Spring Harbor Laboratory
Tatsuya Hirano is interested in understanding the molecular mechanisms responsible for chromosome assembly and segregation in mitosis. He takes a biochemical approach to this problem. The use of cell-free extracts derived from Xenopus laevis eggs allowed him to identify two multiprotein complexes, condensin and cohesin, that play central roles in chromosome condensation and sister chromatid cohesion, respectively. The major focus of Hirano’s lab is to understand how these protein complexes work at a mechanistic level and how their activities are regulated during the cell cycle. Hirano also uses a bacterial counterpart of condensin/cohesin as a model system and tries to understand evolutionary aspects of higher-order chromatin folding. His research will contribute to a better understanding of how genetic information is packaged and is faithfully transmitted to offspring.
(631) 367-8370, hirano@cshl.org

BERNADETTE C. HOLDENER, Assistant Professor
Ph.D. 1990, University of Illinois at Chicago
Department of Biochemistry and Cell Biology
Bernadette Holdener’s research uses the mouse to understand the genetic regulation of mammalian development. She is interested in many aspects of development, ranging from the earliest tissue differentiation to complex tissue interactions required for organ development. Characterization of existing mouse mutations and the generation of new mutations are central to her studies. Laboratory studies focus on mutations that disrupt early embryonic patterning, mesoderm induction, neural differentiation, and the development of cardiac-neural-crest-derived tissues.
(631) 632-8292, holdener@life.bio.sunysb.edu

NANCY M. HOLLINGSWORTH, Associate Professor
Ph.D. 1988, University of Washington
Department of Biochemistry and Cell Biology
Nancy Hollingsworth studies chromosome structure and function during meiosis in the budding yeast, Saccharomyces cerevisiae. In order for diploid cells to generate haploid gametes, chromosomes undergo two divisions following just a single round of DNA replication. Proper segregation of homologous chromosomes at the first meiotic division requires that the chromosomes become physically associated by formation of a multi-protein structure called the synaptonemal complex and undergo recombination. Hollingsworth’s lab uses genetic approaches to identify genes important for synaptonemal complex formation and recombination and then combines genetic, biochemical, and cytological techniques to figure out what the proteins encoded by the genes are doing in the cell. Studying meiosis in a genetically tractable organism such as yeast has been extremely useful in identifying genes important in human reproduction as well, since the process of meiosis is highly conserved throughout evolution.
(631) 632-8581, nhollin@notes.cc.sunysb.edu

Z. JOSH HUANG, Assistant Professor
Ph.D. 1994, Brandeis University
Cold Spring Harbor Laboratory
Josh Huang directs his research at the cellular and molecular mechanisms underlying the experience-dependent development and plasticity of the neocortex. The Huang lab creates transgenic mice to test the role of specific genes in this process, and labels specific classes of neurons in their neocortical circuits so that the morphology and activity of the neurons can be studied with electrophysiological and imaging techniques. Using transgenic mice that overexpress the brain-derived neurotrophic factor, Huang has shown that BDNF is a key regulator of the critical period, a time window in early life when the cortex is particularly sensitive to the influence of experience. Huang’s lab has developed Cre/LoxP recombination-activated markers to label subpopulations of GABAergic interneurons, using cell type-specific promoters and green fluorescent proteins that facilitate the study of different classes of interneurons in living tissue. Huang tests the influence of neuronal activity and sensory experience on the development of these interneurons, and uses genetic manipulations to decipher the underlying molecular mechanisms. Using these approaches, Huang hopes to elucidate the molecular basis of how sensory experiences shape specific components of neocortical circuits.
(631) 367-8455, huangj@cshl.org

DAVID JACKSON, Assistant Professor
Ph.D. 1991, University of East Anglia
Cold Spring Harbor Laboratory
David Jackson studies the mechanisms of shoot morphogenesis in plants using a combination of genetics and cell biology. Plants have a unique mode of development by which they use pools of stem cells called meristems to initiate new organs throughout their lifecycle. By using model genetic systems such as maize and Arabidopsis, the mechanism by which the shoot meristem functions in self-maintenance and in organ initiation is being investigated. It is known that cell-to-cell communication is important for meristem function, and Jackson’s lab is studying the intercellular trafficking of proteins that are required for meristem function. The lab is also characterizing and isolating other genes that regulate plant form through the effects on specific aspects of meristem function. Some of these genes may play an important role in determining crop plant yield.
(631) 367-8467, jacksond@cshl.org

LEEMOR JOSHUA-TOR, Associate Professor
Ph.D. 1991, The Weizmann Institute of Science
Cold Spring Harbor Laboratory
Leemor Joshua-Tor studies the molecular basis of cell regulatory processes in terms of molecular recognition. In her research, her lab uses tools of structural biology and biochemistry in a combined approach to look at proteins, protein complexes, and protein-nucleic acid complexes associated with these processes. Through X-ray crystallography, an accurate three-dimensional structure of individual proteins, their complexes, and the interactions in which they are involved is determined. The lab uses biochemistry to study properties predicted by protein structure and use information from molecular biology and genetics in collaborative efforts to study protein function. Joshua-Tor’s current efforts center on two distinct themes. The first involves structural studies of complexes involved in DNA regulatory processes (replication and transcription). The second is concerned with the regulation of proteolysis in processes such as apoptosis and in an evolutionarily conserved family of self-compartmentalizing intracellular proteases, the bleomycin hydrolases. With the bleomycin hydrolases, the lab is also investigating the structural basis for tumor cell drug resistance to bleomycin and the link to Alzheimer’s disease.
(631) 367-8821, leemor@cshl.org

MAURICE KERNAN, Assistant Professor
Ph.D. 1990, University of Wisconsin
Department of Neurobiology and Behavior
Maurice Kernan worked at the University of California at San Diego before joining Stony Brook’s Neurobiology department in 1995. He is a member of the Center for Developmental Genetics and holds a Pew Scholarship in the Biomedical Sciences.
Kernan’s laboratory uses the powerful genetic model system Drosophila to study the senses of touch, hearing, and proprioception. Mutations that cause touch-insensitivity, deafness, and uncoordination identify genes that are needed for the differentiation or function of mechanosensory cells and organs. Electrophysiological recording from the sense organs identifies those mutants with transduction defects, and genetic mapping and molecular cloning enable the affected genes and proteins to be isolated and described. Current projects include studies of an extracellular protein that links nerve endings to external sensory structures, and a centrosomal protein involved in the differentiation of both ciliated neurons and sperm cells.
(631) 632-9964, mkernan@notes.cc.sunysb.edu

JAMES KONOPKA, Associate Professor
Ph.D. 1985, University of California at Los Angeles
Department of Molecular Genetics and Microbiology
James Konopka’s lab studies the signal transduction pathways that regulate cell growth and development. One specific interest is in the function of the large family of G protein-coupled receptors that includes the photoreceptors, adrenergic receptors, and chemokine receptors. In particular, his lab studies the G protein-coupled mating pheromone receptors (STE2) that induce conjugation in the yeast Saccharomyces cerevisiae. These studies, which take advantage of sophisticated genetic approaches, can be applied to this organism. For example, constitutively active and dominant-negative receptor mutants have revealed new insights into receptor signaling. Similar experimental approaches are now being used to study human receptors expressed in yeast. A second area of interest is in the mechanisms that control morphogenesis of the yeast Candida albicans. During infection by this opportunistic pathogen, cells form elongated hyphae that adhere to host cells and penetrate into underlying tissues. Interestingly, the components that signal this morphological switch show remarkable similarity to those that stimulate conjugation in S. cerevisiae. Therefore, Konopka’s lab is applying information gained from analysis of S. cerevisiae to determine the molecular mechanisms underlying C. albicans pathogenesis.
(631) 632-8715, konopka@ms.cc.sunysb.edu

ADRIAN R. KRAINER, Professor
Ph.D. 1986, Harvard University
Cold Spring Harbor Laboratory
Adrian Krainer’s research focuses on the mechanisms and regulation of messenger RNA splicing in human cells. Biochemical and molecular approaches are used to identify and characterize some of the numerous protein components of the spliceosome and to understand how these components participate in splicing catalysis, splicing fidelity, and the regulation of gene expression by alternative splicing. Structure and function analysis of splicing components, such as RNA-binding proteins of the SR and hnRNP A/B protein families, and the protein serine/threonine phosphatase PP2Cgamma are used to dissect the molecular mechanisms of spliceosome assembly and splice-site selection. His laboratory is also studying the mechanisms by which single point mutations in exons result in exon skipping, thereby causing a variety of genetic diseases. For example, a single-nucleotide difference between the SMN1 and SMN2 survival-of-motor neuron genes, which are involved in the neurodegenerative disease spinal muscular atrophy, and a nonsense mutation in the BRCA1 breast-cancer susceptibility gene causes inappropriate skipping of the mutant exon by inactivating exonic splicing enhancers recognized by the SR protein SF2/ASF.
(631) 367-8417, krainer@cshl.org

JANET LEATHERWOOD, Assistant Professor
Ph.D. 1993, Johns Hopkins University
Department of Molecular Genetics and Microbiology
Janet Leatherwood studies how cyclin-dependent kinases (CDKs) signal a cell to copy its genome and divide. CDKs are master regulators of the eukaryotic cell cycle and control many different events including DNA replication, cell shape changes, transcription programs, mitotic spindle formation, and chromosome condensation.
The main goal of Leatherwood’s lab is to understand CDK regulation of DNA replication in a simple eukaryote, the fission yeast Schizosaccharomyces pombe. The fission yeast cell cycle is driven by a single cyclin-dependent kinase known as Cdc2. One of the most important things Cdc2 does is to coordinate DNA replication with growth and division. To achieve this, Cdc2 has two seemingly opposite activities—Cdc2 acts positively to trigger DNA replication, then it acts negatively to prevent re-initiation of DNA replication. Leatherwood and others have identified direct links between Cdc2 and DNA replication initiation complexes. Her lab is using yeast genetics and biochemistry to learn how these links may direct Cdc2 to control DNA replication.
(631) 632-9644, jleatherwood@ms.cc.sunysb.edu

WILLIAM LENNARZ, Professor and Chair
Ph.D. 1959, University of Illinois
Department of Biochemistry and Cell Biology
William Lennarz is interested in understanding several steps involved in glycoprotein synthesis, including N-glycosylation and protein folding, as well as the functions of the glycan chains. He uses yeast, a simple eukaryotic organism that can be genetically manipulated, to study glycoprotein assembly. More specifically, Lennarz investigates the enzymatic processes of oligosaccharide addition and removal that occur in nascent polypeptides and misfolded glycoproteins, respectively. In addition, PDI, the enzyme that catalyzes folding and disulfide bond formation in glycoproteins, is being studied.
(631) 632-8560, wlennarz@notes.cc.sunysb.edu

SCOTT W. LOWE, Professor
Ph.D. 1994, Massachusetts Institute of Technology
Cold Spring Harbor Laboratory
Scott Lowe’s research investigates the control of apoptosis and senescence, and how mutations that disrupt these processes impact tumor development and therapy. Lowe’s research has previously shown that p53 tumor suppressor is an important regulator of apoptosis, and, as a result, that p53 mutations can promote oncogenic transformation, tumor progression, and resistance to cytotoxic agents. His laboratory has also demonstrated that oncogenic ras can activate p53 to promote cellular senescence, and that escape from ras-induced cell cycle arrest provides a biologic basis for transforming interactions between ras and immortalizing oncogenes. Finally, his laboratory has exploited a mouse lymphoma model to identify genetic factors involved in chemosensitivity in a physiological setting. Lowe’s current research focuses on four interrelated areas: oncogene activation of p53; p53 action in apoptosis; the initiation and maintenance of oncogene-induced senescence; and the molecular genetics of drug sensitivity and resistance in vivo.
(631) 367-8406, lowe@cshl.org

CRAIG C. MALBON, Professor and Vice-Dean, School of Medicine
Ph.D. 1976, Case Western Reserve University
Department of Pharmacological Sciences
Craig Malbon is a molecular endocrinologist who serves on the National Institutes of Health review committees, editorial boards of leading journals, and has been recognized for his work on signal transduction. Using a broad range of technologies, including molecular and cell biology, transgenic mice, and translational studies in humans, his laboratory is interested in elucidating the genetic basis of developmental and metabolic diseases. Alterations in heterotrimeric G-protein signaling provoke well-known examples of developmental diseases in humans, e.g., McCune Albrights Syndrome, Albrights Hereditary Osteodystrophy, and others. The most recent efforts are aimed at understanding the frizzled gene products that transmit Wnt-signaling in vertebrate development. New technologies are being applied to the study of human diseases searching for polygenic bases of complex developmental and metabolic dysfunction, e.g., diabetes.
(631) 444-3077, craig@pharm.som.sunysb.edu

ROBERTO MALINOW, Professor
M.D., Ph.D., 1984, New York University, University of California at Berkeley
Cold Spring Harbor Laboratory
Roberto Malinow’s research focuses on an understanding of learning and memory by studying the physiology of synapses. Synaptic transmission is studied in rat brain slices, which are complex enough to show glimpses of emergent properties and simple enough to allow hard-nosed biophysical scrutiny. In many experiments, the slices are kept in culture, allowing virally directed expression of proteins of interest. With such a preparation, one can examine the role played by individual proteins in synaptic transmission and plasticity. Synaptic function is measured using patch-clamp electrophysiology and two-photon fluorescence imaging. Much of the work in Malinow’s lab is directed toward an understanding of the mechanisms by which synaptic receptors are inserted in synapses. The philosophy is that synapses have key properties that will provide insight into phenomena at higher levels of complexity.
(631) 367-8416, Malinow@cshl.org

KENNETH B. MARCU, Professor
Ph.D. 1975, University at Stony Brook
Department of Biochemistry and Cell Biology
Kenneth Marcu’s research bridges the fields of gene regulation and recombination, humoral and inflammatory immune responses, signal transduction, and cancer. Inflammatory responses are globally initiated by the NF-kB transcription factor family. NF-kBs are cytoplasmically sequestered by inhibitory factors (IkBs) whose site-specific phosphorylation targets them for ubiquination and subsequent proteasomal destruction. The CHUK/IKKk and IKKk serine/threonine kinases phosphorylate IkBs release their hold on NF-kBs. Marcu’s laboratory is investigating the regulated action of the IKKs, designing screens for anti-inflammatory drugs, and identifying novel NF-kB target genes.
Humoral immune response evolves by remodeling B lymphoid cell receptors (BCRs) and by optimizing foreign antigen recognition and effector cell recruitment for immune complex clearance. The immunoglobulin heavy chain gene constant region (IgCH) gene locus undergoes cytokine inducible breakages, converting IgM antibodies to their high-avidity, high-affinity IgG, IgE, and IgA counterparts. Chromosomal breaks in the IgCH locus, upon rare occasions, fuse with the c-MYC proto-oncogene, which collaborates with other selected genetic alterations leading to lymphatic cancers. Marcu’s laboratory is studying the regulation and molecular requirements for IgCH switch-recombinations
(631) 632-8553, kenneth.marcu@sunysb.edu

ROBERT MARTIENSSEN, Professor
Ph.D. 1986, Cambridge University
Cold Spring Harbor Laboratory
Rob Martienssen’s research involves functional genomics in maize and the model plant Arabidopsis thaliana, making use of transposable elements. Systematic genetrap and enhancer trap mutagenesis has resulted in a large collection of knockout mutations in Arabidopsis, which are being used to analyze an array of genetic processes including organogenesis and the epigenetic behavior of transposons and heterochromatin. Two genes involved in leaf polarity, assymetric leaves and dandelion, are being studied molecularly. Numerous target genes involved in axis specification and cell division have been identified, and a genetic pathway for leaf development has been constructed via epistasis analysis. In maize, a functional genomics system has been developed for reverse genetics of maize genes. This is complemented by a novel method for specifically sequencing the unmethylated gene-containing portion of the maize genome. Martienssen’s lab is using these resources both in genome-wide studies and to analyze specific pathways of organogenesis and plant architecture in this classical genetic system.
(631) 367-8322, martiens@cshl.org

W. RICHARD MCCOMBIE, Associate Professor
Ph.D. 1982, University of Michigan
Cold Spring Harbor Laboratory
The long-range goal of Richard McCombie’s research is to correlate structure and function in complex genomes. McCombie’s approach includes two major components: the application of high-throughput DNA sequence analysis and the improvement of technologies, strategies, and software for DNA sequence analysis. His current work focuses on participating in international collaborative efforts to analyze DNA sequences of the human genome and the genome of Arabidopsis thaliana, a small flowering plant that has become an important model organism for plant molecular biology. With a genome of about 100 million base pairs, its compact size, coupled with the availability of many molecular biology tools for studying gene function in this organism, has made Arabidopsis thaliana the primary target of genome sequencing in plants. Through the efforts of scientists in many countries, including those in the McCombie lab, the Arabidopsis genome will be fully sequenced by the end of 2000. McCombie has also begun an effort to sequence regions of human chromosome 18 as well as specific areas of the human genome that are important in cancer development.
(631) 367-8884, mccombie@cshl.org

UTE MOLL, Associate Professor
M.D. 1985, University of Ulm
Department of Pathology, School of Medicine
Research in Ute Moll’s group revolves around the p53 tumor suppressor and related genes, p73 and p63. Concerning p53 regulation in normal cells, the group investigates p53’s requirement for nuclear access that constitutes an important spatial mechanism of regulating p53’s activity as a transcription factor. Moll’s group was recently involved in identifying a novel leucine-rich NES (nuclear export signal) located within the tetramerization domain. This NES can mediate nuclear-cytoplasmic shuttling of p53 in the absence of mdm2 through association with the export receptor CRM1. The model links p53 function with localization. Regulated tetramerization of p53 occludes its NES, thereby ensuring nuclear retention of the active DNA-binding form.
Concerning mechanisms of p53 inactivation in human cancers, Moll and her students discovered a class of inactivating lesions that result in nuclear exclusion of wild type p53 in breast cancer, colon cancer, and neuroblastoma (NB). The group identified the cytoplasmic sequestration not as static but showed that p53 is subject to continuous nuclear-cytoplasmic shuttling with predominant nuclear export (hyperactive export).
(631) 444-2459, umoll@path.som.sunysb.edu

AARON NEIMAN, Assistant Professor
Ph.D. 1994, University of California at San Francisco
Department of Biochemistry and Cell Biology
Research in Aaron Neiman’s lab is focused on understanding the molecular mechanisms controlling the rearrangement of intracellular membranes during differentiation. The model system used to approach these questions is the process of sporulation in the baker’s yeast, Saccharomyces cerevisiae. The formation of spores requires a developmentally programmed reorganization of the secretory pathway in which the mechanisms of vesicle formation, transport, and fusion are coordinately altered. A combination of genetic, cell biological, and biochemical techniques are used to identify genes required for this process and to elucidate the function of the proteins encoded by these genes.
(631) 632-1543, aaron.neiman@sunysb.edu

Andrew Neuwald, Assistant Professor
Ph.D. 1987, University of Iowa
Cold Spring Harbor Laboratory
Andrew Neuwald’s research centers on the development of new statistical and algorithmic methods combined with their application to the classification and modeling of protein domains. The goal of Neuwald’s lab is to detect distant relationships between protein sequences and to model the conserved features of protein families, so that the structure and function of poorly characterized proteins may be more accurately predicted. If evolution is life’s version of the Big Bang—an expansion of protein families across “sequence space” starting from relatively few primordial proteins—then an important task in computational biology is to better understand this protein universe.
Neuwald’s immediate objective is the construction of a comprehensive database of domain models that is tailored to individual protein families. To accomplish this, his lab is developing automated methods for constructing multiple sequence alignments starting from single sequences, improved statistical models of protein domains, and new database-search procedures. Once completed, this database will be available to other biomedical scientists for routine similarity searches.
(631) 367-6802, neuwald@cshl.org

NANCY C. REICH, Associate Professor
Ph.D. 1983, University at Stony Brook
Department of Pathology
Nancy Reich’s research focuses on the study of the mechanisms by which cells respond to their environment. One aspect of her research is the physiological response of cells to cytokine hormones. Cytokines bind to cell surface receptors and transmit a signal to the nucleus that activates transcription of a specific set of genes. This signal transduction pathway initiates with the activation of tyrosine kinases and phosphorylation of latent cytoplasmic transcription factors called signal transducers and activators of transcription (STATs). Phosphorylation of the STATs promotes translocation to the nucleus and binding to specific DNA target sites of induced genes. Another aspect of Reich’s research is the defense response of cells to viral infection. Her investigations have led to the discovery of a latent transcription factor that is activated following viral infection and serves a role in innate immunity and host survival.
Reich’s present work is directed at analyzing the molecular mechanisms that regulate gene expression in response to cytokines or viral infection in both mammalian and Drosophila systems.
(631) 444-7504, nreich@path.som.sunysb.edu

CLINTON RUBIN, Professor
Ph.D. 1983, Bristol University
Departments of Anatomy, Bioengineering, and Orthopaedics
Clinton Rubin’s work is targeted toward understanding the cellular mechanisms responsible for growth, healing, and homeostasis of bone. More specifically, he is interested in how biophysical stimuli (i.e., mechanical, electrical, temperature, magnetic, pressure) mediate these responses. The clinical significance of this work is applicable to the inhibition of osteopenia, the promotion of bony ingrowth into prostheses or skeletal defects, and the acceleration of fracture healing. These goals are approached via interdisciplinary studies at the biochemical, molecular, cellular, tissue, organ, computational (e.g., FEM), and clinical levels.
(631) 632-8521, clinton.rubin@sunysb.edu

STEVE SKIENA, Associate Professor
Ph.D. 1988, University of Illinois, Urbana-Champaign
Department of Computer Science
Steven Skiena is a computer scientist interested in computational biology and bioinformatics. His core expertise is in the design and analysis of combinatorial algorithms and their applications. Within the field of computational biology, he has worked on algorithmic problems associated with DNA chips, particularly new technologies for sequencing by hybridization (SBH) and interpreting gene expression data.
Skiena has also developed more efficient split-synthesis procedures in combinatorial chemistry, and STROLL, a fragment assembler for genome-level DNA sequencing
projects. He is the author of The Algorithm Design Manual, published by
Springer-Verlag.
(631) 632-9026, skiena@cs.sunysb.edu

JACEK SKOWRONSKI, Associate Professor
M.D. 1980, Ph.D. 1981, Lodz Medical School
Cold Spring Harbor Laboratory
Research in Jacek Skowronski’s lab focuses on the mechanisms involved in induction of AIDS by human and simian immunodeficiency viruses (HIV and SIV). In particular, Skowronski studies the structure and function of the viral protein Nef, an important player in the induction of AIDS. In cultured T lymphocytes, the cells that become depleted in AIDS, Nef disrupts expression of the T cell receptor (TCR) and TCR-initiated signal transduction, and it alters the expression of major histocompatibility complex I molecules. Disruption of these T lymphocyte functions by Nef is likely to be involved in the disruption of host immune responses, which is characteristic of AIDS.
The Skowronski lab combines two complementary approaches to address the function of Nef. The molecular genetic approach examines how Nef affects T lymphocyte function and identifies the cellular targets involved. The second approach, involving collaborative experiments, addresses the importance of these molecular interactions for AIDS pathogenesis by studying SIV-infected rhesus monkeys and by characterizing Nef proteins isolated directly from HIV-1 infected people. Results from these studies will facilitate the rational design of drugs that disrupt the Nef functions required for AIDS pathogenesis.
(631) 367-8455, skowrons@cshl.org

STEVEN O. SMITH, Professor and Director, Center for Structural Biology
Ph.D. 1985, University of California at Berkeley
Department of Biochemistry and Cell Biology
Steven Smith is the Director of Structural Biology in the Centers for Molecular Medicine. His research involves understanding in structural and chemical terms how membrane proteins function. His work focuses on the molecular mechanisms of signal transduction by G protein-coupled receptors and receptor tyrosine kinases, and the mechanism of selectivity and gating by ion channel proteins. His research on signal transduction mechanisms mediated by protein conformational changes has involved the visual pigment rhodopsin, a seven-transmembrane helix receptor in vertebrate rod cells responsible for vision in dim light, and CCR5, one of the co-receptors for entry of HIV into T-cells. Current projects involving signal transduction mediated by receptor oligomerization focus on two receptor proteins—the neu or erbB-2 receptor and the platelet-derived growth factor (PDGF) receptor—that can be constitutively activated through interactions involving their transmembrane domains. Finally, structure-function studies are in progress on phospholamban, a 52-residue ion channel protein found in cardiac sarcoplasmic reticulum (SR) that regulates calcium levels across the SR membrane.
(631) 632-1210, steven.o.smith@sunysb.edu

DAVID L. SPECTOR, Professor
Ph.D. 1980, Rutgers University
Cold Spring Harbor Laboratory
The focus of David Spector’s research centers on understanding the spatial organization of gene expression. While much information is available from in vitro studies about the factors involved in gene expression, and in particular RNA processing, much less is known about how these factors find their substrates in the living cell. Spector’s laboratory has taken a molecular/cell biological approach to elucidate the intranuclear dynamics and signals involved in the movement of RNA processing factors from assembly/modification sites to sites of active transcription. To complement their cell biological studies, they have taken a biochemical approach and purified and biochemically characterized a nuclear structure, interchromatin granule clusters, enriched in pre-mRNA processing/transcription factors. This interdisciplinary approach will establish the in vivo parameters necessary for efficient gene expression and will serve as the basis from which to study alterations in nuclear function related to various diseases.
(631) 367-8456, spector@cshl.org

ARNE STENLUND, Associate Professor
Ph.D. 1984, Uppsala University, Sweden
Cold Spring Harbor Laboratory
Arne Stenlund studies the DNA replication properties of papillomaviruses, a very large family of viruses that infect and transform the basal epithelium in their hosts and induce proliferation of cells at the site of infection. Certain types of papillomaviruses give rise to tumors that are prone to progress toward malignancy, frequently causing cervical cancer.
Stenlund’s lab has two primary goals: to acquire a detailed understanding of the processes required for DNA replication from the papillomavirus origin of replication, a requirement for understanding the viral life cycle; and to use the papillomavirus replication system to gain a general understanding of DNA replication at the biochemical level. Stenlund is particularly interested in three universally required, fundamental processes for the initiation of DNA replication: site-specific recognition of the origin of replication; local strand separation or distortion; and loading of a replication helicase.
(631) 367-8455, stenlund@cshl.org

ROLF STERNGLANZ, Professor
Ph.D. 1967, Harvard University
Department of Biochemistry and Cell Biology
Rolf Sternglanz uses the budding yeast, Saccharomyces cerevisiae, to identify mutants and characterize genes affecting structure and function of the nucleus. This includes genes encoding proteins involved in gene regulation, DNA replication, or chromatin structure. His research focuses on three areas: the mechanism of transcriptional silencing of the mating-type loci (i.e., a study of the yeast equivalent of heterochromatin), identification of genes encoding histone acetyltransferases, deacetylases, and other histone-modifying enzymes, and the role of the nuclear periphery in regulation of DNA replication and silencing.
(631) 632-8565, rolf@life.bio.sunysb.edu

BRUCE STILLMAN, Professor
Ph.D. 1979, Australian National University
Director, Cold Spring Harbor Laboratory
A native of Australia, Bruce Stillman is a fellow of the Royal Society and recipient of the Order of Australia. His research focuses on the processes that ensure accurate inheritance of genetic material from one cell generation to the next. He has contributed to the discovery of many DNA replication proteins that function to replicate the human genome. Stillman studies the mechanism and cell cycle control of initiation of chromosomal DNA replication in the yeast Saccharomyces cerevisiae and human cells. His laboratory elucidated the structure of chromosomal origins of DNA replication and origin binding proteins. One of these, the Origin Recognition Complex (ORC), facilitates initiation of chromosome DNA replication. ORC also functions as a landing pad for other replication proteins, including Cdc6, the MCM helicase, and cyclin CDKs.
In other research, Stillman has studied the mechanism of inheritance of chromatin and epigenetically determined states of gene transcription. He has shown that this process involves interaction between the chromatin assembly protein CAF-1 and PCNA, a DNA replication protein.
(631) 367-8383, stillman@cshl.org

F. WILLIAM STUDIER, Senior Biophysicist
Ph.D. 1963, California Institute of Technology
Biology Department, Brookhaven National Laboratory
William Studier’s research has centered primarily on bacteriophage T7, including genetic and physical mapping of T7 DNA; functions of T7 genes; control of gene expression; entry into the cell; overcoming host restriction; replication, processing, and packaging of T7 DNA; and structure and assembly of phage particles. Research techniques developed in this work have found wide application, particularly slab gel electrophoresis for analysis of proteins and nucleic acids, and gene expression systems based on T7 RNA polymerase. Of recent interest to Studier is the interaction between T7 RNA polymerase and T7 lysozyme, and the role of this interaction in transcription, replication, DNA packaging, and cell analysis.
Studier’s current work is directed toward structural genomics, the systematic determination of three-dimensional structures for representatives of protein families clustered by similarity in amino-acid sequence. Procedures are being developed for high-throughput X-ray crystallography, starting from genome or cDNA sequences, to build a body of structural information that will facilitate prediction of a reasonable structure and potential function for almost any protein from its coding sequence.
(631) 344-3390, studier@bnl.gov

WILLIAM TANSEY, Assistant Professor
Ph.D. 1991, University of Sydney, Australia
Cold Spring Harbor Laboratory
William Tansey researches the fundamental aspects of transcription factor regulation and cell cycle control, focusing on how these processes go awry in cancer. Current research in Tansey’s lab centers on discovering mechanisms by which transcription factors are destroyed. Many of the transcription factors involved in cell proliferation are short-lived proteins that are constantly synthesized and then degraded rapidly by ubiquitin-mediated proteolysis. Rapid destruction of these potent transcription factors allows their activity to be maintained at levels appropriate for controlled cell proliferation.
As a paradigm for the regulated destruction of transcription factors, Tansey studies the product of the Myc oncogene, because it is an important human oncoprotein that directly activates genes required for cell cycle progression. Since little is known about how Myc is destroyed in vivo, Tansey’s group seeks to identify the cellular machinery that targets Myc for ubiquitin-mediated destruction and to learn how the regulation of Myc turnover and the loss of control of this process relates to human cancer.
(631) 367-8455, tansey@cshl.org

DAVID G. THANASSI, Assistant Professor
Ph.D. 1995, University of California at Berkeley
Department of Molecular Genetics and Microbiology
David Thanassi is interested in understanding the assembly and secretion of virulence factors required for pathogenic bacteria to cause disease. His research focuses on pilus biogenesis by uropathogenic Escherichia coli, a major cause of upper and lower urinary tract infections. Pili are essential virulence organelles that radiate out from the bacterial cell surface, mediating recognition and binding of host cells. In particular, his lab is interested in understanding the structure and function of an essential pilus assembly protein termed “the usher,” an outer membrane protein that directs pilus assembly and is required for secretion of pili to the cell surface. Pilus biogenesis provides an excellent model system for studying virulence factor secretion and for dissecting basic biological processes such as protein-protein interactions, protein targeting, and the ordered assembly of complex structures. A goal of the Thanassi lab is to apply knowledge gained from the study of pilus biogenesis and virulence factor secretion toward the development of novel antimicrobial agents.
(631) 632-4549, dthanassi@ms.cc.sunysb.edu

GERALD H. THOMSEN, Associate Professor
Ph.D. 1988, Rockefeller University
Department of Biochemistry and Cell Biology
Gerald Thomsen studies vertebrate embryonic development and its fundamental importance to general biological knowledge and to medicine. As the various model organism genome projects progress, embryology is poised to play an increasingly important role in puzzling out the function of newly discovered genes. Thomsen’s research focuses on the transforming growth factor-B (TGFB) in developing vertebrate embryos of the frog, Xenopus laevis. The Thomsen lab is interested in how members of the TGFB family, such as Vg1, activin, and bone morphogenetic proteins (BMPs) function to control differentiation and growth of tissues, particularly tissues that form blood, muscle, the heart, head, and nervous system.
Thomsen has characterized the biochemical mechanisms of how various TGFBs trigger their effects in cells, discovering that BMPs directly trigger blood differentiation. His lab also studies the role that TGFBs play in the control of human cell growth and cancer.
(631) 632-8536, gerald.h.thomsen@sunysb.edu

STYLIANI-ANNA E. TSIRKA, Assistant Professor
Ph.D. 1989, Aristotelian University of Thessaloniki
Department of Pharmacological Sciences
The focus of Stella Tsirka’s work is the signaling events and cell-cell communication after normal or exaggerated stimulation of the central nervous system. Stimulation within the physiological levels leads to structural changes in the brain (like neurite outgrowth or retraction); overstimulation to the neurons leads to neuronal cell death. The experimental system used for neuronal death is excitotoxicity, which models the mechanism of death observed in several neurodegenerative diseases. A handle to study these events is the extracellular serine protease tissue plasminogen activator (tPA). Stella Tsirka has identified a functional role for tPA, namely that it promotes neuronal death in the mouse brain. tPA is expressed both by neurons and microglia, and it affects the two cell types using different biochemical pathways: tPA promotes neuronal cell death via its proteolytic activity, but mediates microglial activation via a non-proteolytic pathway. The two cell types interact with each other and the mechanisms of this interaction is being investigated.
(631) 444-3859, stsirka@mail.psychiatry.sunysb.edu

TIMOTHY TULLY, Professor
Ph.D. 1981, University of Illinois
Cold Spring Harbor Laboratory
Following postdoctoral training in Neurogenetics at Princeton University and Molecular Genetics at the Massachusetts Institute of Technology, Tim Tully joined the Biology faculty at Brandeis University in 1987. In 1991, he joined Cold Spring Harbor
Laboratory as part of its new focus on neuroscience.
Tully’s research on a Drosophila model system for simple associative learning began as a postdoctoral student in the laboratory of Dr. W.G. Quinn at Princeton University. Tully showed that Pavlovian learning in flies exhibits behavioral properties similar to those observed in vertebrates and then characterized memory retention in
several single-gene mutants. This work has produced a “genetic dissection” of memory formation into multiple temporal phases. In 1995, Tully and co-workers published the first demonstration of enhanced memory in genetically engineered animals. Tully received a Decade of the Brain Award in 1999 from the American Association of Neurology in recognition of this neurogenetic breakthrough.
(631) 367-8875, tully@cshl.org

LINDA VAN AELST, Associate Professor
Ph.D. 1991, Catholic University of Leuven
Cold Spring Harbor Laboratory
Research in Linda Van Aelst’s lab centers on signal transduction pathways that control biological activities, such as cell proliferation, morphogenesis, tumorigenesis, and metastasis. She studies the roles of the GTPases Ras and Rac in signal transduction. Cellular Ras genes are frequently activated by mutation in a wide variety of human cancers. Van Aelst has shown that the serine/threonine kinase Raf interacts directly with Ras and is essential for Ras-mediated transformation.
Van Aelst’s major objectives are to dissect the physiological roles of Rac and its interacting proteins and to characterize the proteins that mediate the activities of Ras and Rac. To that end, her lab has set out to identify physiologically relevant targets of Ras and Rac, and to characterize genetically the different Rac signal-transduction pathways involved in cell-growth control.
(631) 367-8455, vanaelst@cshl.org

MICHAEL WIGLER, Professor
Ph.D. 1978, Columbia University
Cold Spring Harbor Laboratory
Michael Wigler examines cancer genes and the proteins involved in signal-transduction pathways. The Wigler lab uses yeast cells and mammalian cells in culture to study these oncogenes. To discover new cancer genes, his lab has developed representational difference analysis (RDA), a method that selects restriction fragments that are present in one of only two DNA populations, or that are more numerous in one than in another.
Wigler has used RDA to detect genetic abnormalities that accumulate in the genomes of tumor cells, including DNA amplifications, rearrangements, loss of heterozygosity, and homozygous deletions. Using RDA, he discovered homozygous deletions on chromosome 10, and through positional cloning of this region, identified PTEN, a new tumor-suppressor gene that encodes a protein phosphatase. Wigler and his group are also exploring the combination of representational approaches of genomic analysis and microarray technology to develop methods for high-resolution scanning of the genomes of cancer cells.
(631) 367-8377, wigler@cshl.org

ECKARD WIMMER, Professor
Dr.rer.nat. 1962, University of Gottingen
Department of Molecular Genetics and Microbiology
Eckard Wimmer’s group studies human pathogenic viruses whose genomes are single- stranded RNA and serve, after invasion into the host cell, as messenger RNA (plus-stranded RNA viruses). These include enteroviruses, particularly polio virus, and
coxsackie viruses, and hepatitis C virus (HCV), a flavivirus. With respect to virion structure, replication, and pathogenesis, enteroviruses and HCV could not be more different. The polio virus is non-enveloped with a short lytic infectious cycle that only rarely (two percent of infections) causes a neurologic disease (poliomyelitis). It can be produced in large quantities and can be studied in transgenic mice. HCV, an enveloped virus that cannot be propagated in tissue culture cells or experimental animals to reasonable quantities, causes chronic liver disease (70 percent of infections) that, after many years, is often lethal. And yet the general gene organization of these viruses is remarkably similar. It is the objective of Wimmer’s research group to decipher the molecular basis of replication and pathogenesis of enteroviruses and HCV (cellular receptors, parameters of tissue tropism, control of gene expression, genome replication).
(631) 632-8787, ewimmer@ms.cc.sunysb.edu

 

MICHAEL ZHANG, Associate Professor
Ph.D. 1987, Rutgers University
Cold Spring Harbor Laboratory
Michael Zhang is the Director of the Bioinformatics course at the Watson School of Biological Sciences. The long-term goal of research in his lab is to use mathematical and statistical methods to identify functional elements in eukaryotic genomes, their control, and regulatory elements. Research of the genome, the program book of a life, will lead to eventual decoding of the entire genetic language of life and its grammar. Driven by the Human Genome Project, Zhang’s interest is on gene-finding.
Since most eukaryotic genes are split by intervening sequences (called introns) after transcription of a gene into a precursor mRNA, the introns have to be spliced out and the remaining coding fragments (called exons) have to be joined together as a mature mRNA before it can be translated into protein. Therefore, the key of gene-finding is to identify these exons. Constitutive coding exons are relatively easy to identify; the greatest challenge lies in the identification of end exons and alternatively spliced exons.
(631) 367-8393, mzhang@cshl.org

YI ZHONG, Associate Professor
Ph.D. 1992, University of Iowa
Cold Spring Harbor Laboratory
Yi Zhong uses Drosophila as a model to study molecular and neural bases of learning and memory. The powerful genetic tools uniquely amenable to Drosophila have enabled isolation of a number of learning and memory mutants over the past two to three decades. He believes that molecular, behavioral, and anatomical insights resulting from the studies of these mutants in many laboratories have built a foundation to take our understanding of learning and memory to the next level.
One area of study is directed to establish Drosophila models of neural disorders that impair learning and memory, including Neurofibromatosis 1 (NF1) and presenilin genes. NF1 is a frequent neurogenetic disorder identified by tumors in peripheral nervous tissues as well as the learning defect. Mutations of the presenilin gene cause early onset of Alzheimer’s disease.
Another area revolves around the screening of mutants that show enhanced learning resulting from overexpression of genes. Zhong hopes that such mutagenesis will not only help in understanding the mechanisms of learning and memory, but also provide drug targets for improving human learning and memory.
(631) 367-6811, zhongyi@cshl.org

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