2005 Research Highlights...

Reactome (www.reactome.org), a collaboration between Lincoln Stein,  the European Bioinformatics Institute (EBI) and the Gene Ontology Consortium, is a web-accessible resource for curated information about biological processes.  Reactome is organized like a review journal. Bench biologists can create modules that summarize a particular aspect of their field. Currently summations include DNA replication, transcription, translation, intermediary metabolism, the cell cycle, RNA splicing and hemostasis. The database is then used to drive a web site that can be browsed like a textbook or searched with queries to discover pathways and connections.  Joshi-Tope, et al. (2005). Nucleic Acids Res 33, D428-432.
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In a collaboration between Scott Powers, Scott Lowe, Greg Hannon and colleagues at MSKCC, investigators demonstrated that a microRNA cluster can modulate tumour formation, the first implication that non-coding RNA’s can act as oncogenes.   He, et al. (2005).  Nature 435, 828-833.
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David Spector’s lab reports a novel mechanism for regulation of gene expression through retention of an mRNA precursor in the nucleus.  Under conditions where protein production is needed immediately, the RNA is clipped, transported and expressed rapidly.  Prasanth, et al. (2005).  Cell 123, 249-253.
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Greg Hannon’s lab generated large-scale-arrayed, sequence-verified libraries comprising more than 140,000 second-generation short hairpin RNA expression plasmids, covering a substantial fraction of all predicted genes in the human and mouse genomes. These libraries are available to the scientific community. Silva, et al. (2005). Nat Genet 37, 1281-1288.
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Lincoln Stein and the International HapMap Consortium, release the first comprehensive collection of their "haplotype map" or HapMap.  This consists of more than 1 million unique markers of human genetic variation gleaned from 270 individuals from four worldwide populations. This information can be used to help the identification of gene involved in common diseases such as cancer, heart disease, diabetes and asthma. Thorisson, et al. (2005).  Genome Res 15, 1592-1593.
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2004 Research Highlights...

David Spector developed the first system for visualizing gene expression - from DNA to RNA to protein - within living cells. This system can be used to observe and interpret dynamic changes in the cellular steps during DNA replication, transcriptional regulation, pre-mRNA splicing and mRNA nuclear export. Janicki, et al. (2004) From silencing to gene expression: real-time analysis in single cells. Cell. 116:683-98.
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Mike Wigler and colleagues reported the discovery of high frequency copy number polymorphisms (CNPs) in the human gene pool that may underlie considerable phenotypic variation and disease susceptibility.  Sebat, et al. (2004). Large-scale copy number polymorphism in the human genome. Science 305, 525-528.
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Grigori Enikolopov showed that nitric oxide is a regulator of hematopoietic stem cell activity, suggesting that suppression of NO synthase activity may allow expansion of the number of hematopoietic stem and progenitor cells or neutrophils for therapeutic purposes. Michurina, et al. (2004). Mol Ther. 10:241-8
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2003 Research Highlights...

Mike Wigler and Rob Lucito are using ROMA (Representational Oligonucleotide Microarray Analysis) to identify genomic variation between cancer samples and normal cells from the same patient.  Using this technique, which was developed in the Wigler laboratory, they have uncovered a striking collection of chromosomal deletions and amplifications associated with breast cancer. These studies will be extended to survey a large number of breast, ovarian, and pancreatic tumors and cell lines, as well and leukemia and lymphomas.  Results from these analyses should provide great insights into the molecular nature of cancer.   Lucito, et al. (2003). Genome Res 13:2291-2305. Click here for more on ROMA and cancer gene discovery.
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Leemor Joshua-Tor and Greg Hannon collaborated to solve the structure of the Argonaute protein.  Argonaute has one domain that binds double stranded RNA and another domain that is structurally similar to the nuclease RNaseH, suggesting that Argonatue is the enzyme that embodies the “slicer” activity of RISC and thus carries out the final step of RNA interference (mRNA cleavage and destruction).  Song, et al. (2003). Nat Struct Biol 10, 1026-1032; Song, et al. (2004).  Science 305, 1434-1437.
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Nick Tonks, in collaboration with David Barford (Institute of Cancer Research, London), showed that oxidation results in the formation of a reversible covalent link between the catalytic cysteine and nitrogen on an adjacent main chain serine of a protein tyrosine phosphatase (PTP1B).  This reaction is accompanied by a large conformational change that inhibits substrate binding.  This previously unrecognized mechanism has many implications of understanding the role of redox signaling in signal transduction and gene expression. Salmeen, et al. (2003). Nature 423, 769-773.     
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Scott Lowe describes changes in nuclear morphology and chromatin structure that occur when a cell enters senescence, a state in which cells are alive but cease proliferating indefinitely. Senescence is characterized by changes in DNA architecture similar to, but distinct from, the heterchromatin found in pericentric regions of chromosomes. Formation of SAHF is mediated by the tumor suppressor Rb, and is accompanied by silencing of gene expression in the region. These results provide a molecular explanation for the stability of the senescent state, as well as new insights into pathways that can be explored for cancer therapy. Narita et al., Cell. 2003 Jun 13;113(6):703-16.   
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Scott Powers (Tularik) along with Mike Wigler, Scott Lowe and Dick McCombie (CSHL) discover and characterize a novel oncogene, KCNK9, a potassium channel gene that is expressed at abnormally high levels in nearly 50% of breast cancers and 35% of lung cancers. Mu et al., Cancer Cell 2003 Mar;3(3):297-302.     
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Scott Lowe used RNAi to stably suppress expression the p53 tumor suppressor gene in hematopoietic stem cells and organs derived from those cells. Several shRNA expression vectors inhibited p53 activity and produced phenotypes as predicted based on experiments in which the p53 gene itself was deleted. In all cases, the severity and type of disease correlated with the extent to which specific shRNAs inhibited p53 activity. Hemann et al., Nat Genet 2003 Mar;33(3):396-400.
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Greg Hannon of Cold Spring Harbor Laboratory and Thomas Rosenquist of Stony Brook University used genetic engineering to create mouse embryonic stem cells in which RNAi was targeted to a particular gene. This is the first demonstration that RNAi, known to work well to specifically knock out gene expression in vitro, can be used as a tool to manipulate gene expression in vivo. This approach should be applicable to many genes, and would permit the rapid identification of possible phenotypes or gene expression patterns for newly identified cancer genes. Carmell et al., Nat Struct Biol 2003 Feb;10(2):91-2.        
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Adrian Krainer and Luca Cartegni designed small chimeric effectors comprising a minimal synthetic RS domain covalently linked to an antisense moiety that targets an exon by Watson-Crick base pairing. These synthetic effectors can mimic the functions of SR proteins and specifically restore wild type splicing when directed to defective BRCA1 or SMN2 pre-mRNA transcripts. Since many disease-associated mutations also affect pre-mRNA splicing, usually causing inappropriate exon skipping, this general approach can be used as a therapeutic strategy to correct splicing defects responsible for numerous diseases. Cartegni L & Krainer AR. Nat Struct Biol 2003 Feb;10(2):120-5.    Click here for more on correction of mRNA splicing defects with synthetic molecules      
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2002 Research Highlights...

Masaaki Hamaguchi and Mike Wigler discover a new cancer gene using RDA technology. The new gene, DBC2, is found to be deleted in over half of human breast cancers. Hamaguchi et al., Proc Natl Acad Sci U S A 2002 Oct 15;99(21):13647-52.
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A high-quality draft sequence of the mouse genome was completed by an international collaboration that included W. R. McCombie at Cold Spring Harbor Laboratory. The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Waterston et al, Nature 2002 Dec 5;420(6915):520-62.
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2001 Research Highlights...

Shiv Grewal showed that modifications of histone H3 play a central role in determining the ability of large regions of the chromosome to be expressed. These effects on gene expression can be maintained as cells divide, suggesting that, in addition to the precise sequence of nucleic acids, the state of the proteins associated with the DNA can contribute to the expression of inherited traits. Nakayama et al., Science 2001 Apr 6;292(5514):110-3.
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Michael Zhang and colleagues develop a new program, FirstEF, for prediction of the first exon of genes based on recognition of structural and compositional features such as CpG islands, promoter regions and first splice-donor sites. This program can predict first exons with an accuracy of 86%, and provides a new tool for estimation of the total number of genes in the human genome. Davuluri et al., Nat Genet 2001 Dec;29(4):412-7.
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Greg Hannon identifies two ribonucleases that define the mechanism of RNA interference. The first nuclease, Dicer, cleaves double stranded RNA into a 22 bp fragment. This fragment can direct a second nuclease complex, RISC, to destroy complementary messenger RNAs. Dicer contains a region of homology to the Drosophila ARGONAUTE protein (and related proteins in Arabidopsis and C. elegans), which has been genetically linked to RNA interference. Bernstein et al., Nature 2001 Jan 18;409(6818):363-6. 
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Lincoln Stein establishes a database of over one million human Single Nucleotide Polymorphisms (SNP) as part of the international SNP consortium group. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy. Sachidanandam et al., Nature 2001 Feb 15;409(6822):928-33.
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2000 Research Highlights...

Robert Martienssen, W. Richard McCombie, and colleagues report the first complete genome sequence of a plant (Arabidopsis). Tabata et al., Nature 2000 Dec 14;408(6814):823-6.
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Robert Lucito, Michael Wigler and colleagues describe a method for detecting gene copy number fluctuations in tumor cells by microarray analysis of genomic representations. Lucito et al., Genome Res 2000 Nov;10(11):1726-36.
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Adrian Krainer and Michael Zhang discover why particular mutations in the BRCA1 gene cause breast and ovarian cancer. Some of these mutations disrupt "splicing enhancers" and cause skipping of one or more exons during pre-mRNA splicing. Liu et al., Nat Genet 2001 Jan;27(1):55-8.
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Scott Lowe discovers new genes that are mutated in human breast cancer, melanoma, and other cancers. He describes a genetic strategy whereby cancer cells can circumvent the apoptotic pathway and become resistant to chemotherapy. These studies provide new insights into the relationship between cancer genetics and cancer therapy, and provide strong support for the view that tumor genotype is the most important determinant of treatment outcome. Soengas et al., Nature 2001 Jan 11;409(6817):207-11. 
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Leemor Joshua-Tor, Arne Stenlund and their colleagues determine the shape and biochemical properties of the papillomavirus E1 protein binding domain. E1 is required for papillomavirus DNA replication, and the structure of this protein suggests a model for assembly of proteins and initiation of viral replication. Papillomavirus infection is associated with virtually every case of human cervical cancer. Enemark et al., Mol Cell 2000 Jul;6(1):149-5.8 abstract


 
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