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Chromosomes: dynamics, maintenance & evolution


University of Oxford, UK


David Sherratt became committed to a research career in DNA-related molecular biology after attending an 'Xmas Lecture' at his local University when 13 years old. After graduating in Biochemistry at the University of Manchester, he did a Ph.D. on bacterial genetics in the newly formed department of Molecular Biology at the University of Edinburgh (1969). His postdoctoral work was in Don Helinski's lab at UCSD where he studied plasmid ColE1. He then became a faculty member in the University of Sussex (1971), where he furthered investigations of plasmid biology, while initiating programmes on transposition and site-specific recombination mechanisms. In 1980, he took up the Chair of Genetics at Glasgow University and in 1994 was appointed to the Iveagh Chair of Microbiology in the Biochemistry Department, University of Oxford. His research now focuses on bacterial chromosome processing. In 1983 he was elected to membership of EMBO, in 1992 he was elected FRS and in 2003 he was elected to Fellowship of the American Academy of Microbiology.

Title & Synopsis
Bacterial chromosome dynamics

Our research objective is to use multidisciplinary methods to understand the inter-relationships of bacterial chromosome organization, replication and segregation. One mission is to explore in living cells the assembly, action and targeted disassembly of molecular machines in close to real time. The 4.6 Mbp Escherichia coli chromosome has its genetic map recapitulated within cells that are ~2.2 mm long and ~0.7 mm in diameter. In non-replicating cells, the single origin of replication is located close to midcell, with loci on the left chromosome arm disposed sequentially outwards, and right chromosome arm loci disposed sequentially to the right. A region of the replication termination region, which can be less than 45 kb, spans the outside nucleoid edges. Chromosome replication and segregation occur sequentially, with loci separating to different cell halves about 15 min after replication. Interlinking of the newly replicated sister chromosomes, to give precatenanes, is responsible for this short period of sister locus cohesion. TopoIV, acting throughout the cell cycle, removes the precatenanes. At replication initiation, replisomes assemble at activated origins, irrespective of their position in the cell. Sister replisomes separate spatially within 5 min of chromosome replication initiation and then move into separate cell halves as they track along DNA, finally moving back to midcell at replication termination. Cells modified to have 2 replication origins, separated by ~1 Mbp, grow well and initiate replication synchronously at both origins. The composition of in vivo replisomes has been measured by a live cell imaging technique that gives single protein molecule sensitivity, 3 ms temporal resolution and 5 nm spatial precision. Single replisomes contain 3 polymerase molecules, 3 sliding clamps, and a single clamp loader complex and are normally associated with 3- 10 Ssb tetramers.


De Lange

Rockefeller University, US


Titia de Lange was a graduate student with Piet Borst at the Dutch Cancer Institute where she studied antigenic variation in Trypanosoma brucei. After receiving her Ph.D. in 1985, she joined the laboratory of Harold Varmus at the University of California, San Francisco. In 1990, she was appointed to the faculty of the Rockefeller University and promoted to Professor in 1997. Her research is focussed on the function of mammalian telomeres and their role in aging and cancer.

Title and synopsis
How telomeres protect chromosome ends

The TTAGGG repeats of mammalian telomeres protect chromosome ends through their interaction with shelterin. The telomeric repeats are maintained by telomerase, the telomere specific reverse transcriptase that solves the end- replication problem. Here we report on a second telomere replication problem that results in telomeres behaving like common fragile sites. Aphidicolin levels that induce the common fragile sites resulted in human and mouse telomeres showing frequent abnormalities, appearing fragmented or decondensed. This fragile telomere phenotype occurred spontaneously when the shelterin component TRF1 was deleted and was exacerbated by inhibition of the ATR kinase. Telomeres lacking TRF1 activated ATR signaling in S phase, suggesting that TRF1 represses the fragile telomere phenotype by preventing replication problems in telomeric DNA. Furthermore, visualization of replication fork progression in individual telomeric DNA molecules showed that TRF1 promotes replication of telomeric DNA and prevents fork stalling. Two helicases, BLM and RTEL1, which both have the ability to remove the G4 DNA structures from G-rich repeats, were identified as potential factors acting downstream of TRF1 to repress the fragile telomere phenotype. These findings establish that mammalian telomeric DNA challenges DNA replication, creating a second replication problem that is solved by TRF1.



Research Institute, Cancer Research UK


Stephen West is a British citizen, born in the town of Hessle, Yorkshire, in 1952. He studied Biochemistry at Newcastle University before moving to the USA to carry out post-doctoral work with Paul Howard-Flanders in the Department of Molecular Biophysics and Biochemistry at Yale University. In 1985, he moved back to the UK to set up a research group at the Imperial Cancer Research Fund's new Clare Hall Laboratories at South Mimms. He is a Senior Group Leader with Cancer Research UK and Deputy Director of Clare Hall Laboratories. His research has centred on mechanisms of genetic recombination and DNA strand break repair. In particular, he has defined relationships between defective DNA repair processes and human diseases such as inheritable breast cancer and neurological disorders. He has been elected to EMBO, is a Fellow of the Royal Society, and a Fellow of the Academy of Medical Sciences. In 2002 he was awarded the Swiss Bridge Prize Award for Cancer Research, and presented the Leeuwenhoek Prize Lecture of the Royal Society. He is the recipient of the 2007 Louis-Jeantet Prize for Medicine and the 2008 Novartis Prize and Medal from the Biochemical Society.

Title & Synopsis
Defective DNA strand break repair and links to human disease

Defects in basic cellular DNA repair processes have been linked to genome instability, inheritable cancers, premature aging syndromes and neurological diseases. Our understanding of most DNA repair pathways is now well advanced, and it is often possible to pinpoint the underlying defects that lead to disease progression. For example, we now know that the breast cancer tumour suppressor BRCA2 controls the nuclear relocalization and activities of RAD51 protein, a key player in homologous recombination-mediated double-strand break repair. Without efficient homologous recombination, BRCA2-deficient cells exhibit high levels of spontaneous chromosome instability, and an inability to promote the repair of DNA breaks caused by ionizing radiation or radiomimetic drugs. BRCA2 also regulates meiotic recombination through interactions with the meiosis-specific DMC1 protein, suggesting that it acts as a universal regulator of homologous recombination both in mitotic cells and in germ-line cells. Recently a new factor in this BRCA2-regulated pathway of recombinational repair was identified. This protein, GEN1, resolves recombination intermediates (Holliday junctions) a reaction that is essential for proper chromosome segregation. Cleavage occurs by the introduction of symmetrically-related cuts across the junction point, to produce nicked duplex products that can be ligated, in a manner analogous to that exhibited by the E. coli Holliday junction resolvase RuvC. Understanding the molecular basis of inheritable diseases such as those linked to BRCA2 mutations holds promise for the future development of therapies based either on the removal of the causative lesions, or on the sensitization and destruction of damaged cells by the specific targeting of alternative repair pathways.


Signalling pathways in development & cancer

Julian Downward

London Research Institute, Cancer Research UK


Julian Downward obtained his bachelor’s degree in Natural Sciences from Cambridge University and then studied for his Ph.D. in the laboratory of Michael Waterfield at the Imperial Cancer Research Fund in London, where he established in 1984 the link between a retroviral oncogene (v-erbB) and a cellular growth regulatory protein, the EGF receptor. In 1986, he moved to Robert Weinberg’s laboratory at the Whitehead Institute at the Massachusetts Institute of Technology in Cambridge, MA, where he began work on the role of Ras proteins in human cancer. In 1989 he started his own lab at the Imperial Cancer Research Fund, now Cancer Research UK London Research Institute, where his lab has provided insights into the molecular mechanisms of function and regulation of oncogenic proteins of the Ras family and the importance of their mutational activation in human tumours. In 2005 Julian was made a Fellow of the Royal Society, the UK’s national academy of sciences, and became Associate Director of the Cancer Research UK London Research Institute.

Title & Synopsis
Ras & PI 3-kinase signalling pathways in oncogenesis

The RAS oncogenes are very frequently activated in human tumours. As a result, the signalling pathways they control have been well studied, leading to a good understanding of many of the early events involved in their signalling. However, much less is known about the relative importance of the different RAS controlled pathways in the genesis of tumours in vivo, and also about more downstream signalling events. I will describe approaches involving mouse genetics and functional genomics to address both of these issues. In order to find novel targets in RAS signalling pathways, we have undertaken a number of studies using large-scale RNA interference libraries. One has been a screen for genes that cause apoptosis in RAS oncogene addicted cells. In this way a number of pathways have been identified that are important for survival of RAS transformed, but not normal, cells. Some of these have not previously been implicated in RAS signalling. Further investigation indicates that some of these hits reflect true RAS oncogene addiction while others represent acute synthetic lethality of target knock-down with RAS signal. Targeting both mechanisms, synthetic lethality and oncogene addiction, together may provide optimal differential killing of cancer cells relative to normal cells. An example of the potential power of blocking RAS signalling has been provided recently when we introduced point mutations into the gene encoding the phosphatidylinositol 3-kinase p110α, which block its ability to interact with activated RAS. Mice homozygous for the p110α mutation show a very dramatically reduced rate of cancer incidence in two models of RAS oncogene driven tumour formation. Failure of RAS to engage PI 3-kinase results in elevated rates of apoptosis in tumour precursor lesions and consequent failure of tumours to develop. Targeting this interaction may have clear therapeutic potential.


Anne Ridley

Kings College, London, UK


Anne Ridley obtained a B.A. in Natural Sciences (Biochemistry) from the University of Cambridge. She then went to Imperial Cancer Research Fund (now Cancer Research UK) in London to work with Hartmut Land, and obtained a Ph.D. in 1989 (University of London). She was awarded an EMBO postdoctoral fellowship to work in the laboratory of David Page (Whitehead Institute, Cambridge, MA) for a year. In 1990 she moved to the Institute for Cancer Research, London, to work with Alan Hall on Rho and Rac proteins. In 1993 she set up her laboratory at the Ludwig Institute for Cancer Research (University College London Branch), and initiated studies on signalling pathways regulating cell migration. She then moved to King's College London to become Professor of Cell Biology in the Randall Division of Cell and Molecular Biology in 2007.

Title & Synopsis
Rho GTPases in cancer cell adhesion and migration

Rho GTPases are found in all eukaryotes and regulate actin and microtubule dynamics, thereby contributing to multiple cellular functions, including cell migration, vesicle trafficking, and transcriptional regulation. We are investigating the roles of the 20 different mammalian Rho family members and their interacting partners in cancer cell migration and cell-cell adhesion. The mechanisms underlying the roles of different Rho proteins in cancer cell adhesion and migration will be discussed. In particular, the Rho subfamily of GTPases, composed of the closely related members RhoA, RhoB and RhoC, are thought to perform different functions during cancer progression, including tumor cell dissemination. We have found that RNAi-mediated downregulation of RhoA, RhoB or RhoC has different effects on cell morphology and on migration and invasion. The phenotypes are different from that observed after C3 transferase treatment, which inhibits all three isoforms, and point to isoform-specific functions. In addition, we are studying the regulation and function of the Rnd proteins Rnd1, Rnd2 and Rnd3/RhoE, which are less-well characterized members of the Rho family and are unusual in that they do not hydrolyse GTP. Instead, we have found that Rnd3 is regulated by expression levels, phosphorylation and localization. The involvement of the serine-threonine kinases ROCK1 and ROCK2 downstream of Rho and Rnd proteins will be discussed.


Elaine Fuchs

Rockefeller University,US


Elaine Fuchs is the Rebecca C. Lancefield Professor in Mammalian Cell Biology & Development at The Rockefeller University. She is also an Investigator, Howard Hughes Medical Institute. She has published more than 250 papers and is internationally known for her research in skin biology and its human genetic disorders, which include skin cancers and life-threatening genetic syndromes such as blistering skin disorders. She received a Ph.D. in Biochemistry from Princeton University, and then conducted postdoctoral research at the Massachusetts Institute of Technology in the laboratory of Howard Green. She joined the faculty at the University of Chicago, where she stayed for 20 years prior to moving to The Rockefeller University in 2002. Her many awards and honours include the Presidential Young Investigator Award, the Richard Lounsbery Award from the National Academy of Sciences, the Novartis-Drew Award for Biomedical Research, the Dickson Prize in Medicine, the FASEB Award for Scientific Excellence and the Beering Award. She is a member of the National Academy of Sciences, the Institute of Medicine of the National Academy of Sciences, the American Academy of Arts and Sciences and the American Philosophical Society, and she holds honorary doctorates from Mt. Sinai/New York University School of Medicine and from the University of Illinois, Champaign-Urbana. She is also a past President of the American Society of Cell Biology and in summer 2009, she will be President-Elect of the International Society for Stem Cell Research.

Title & Synopsis
Quiescence vs activation: A balancing act in stem cell niches

Stem cells can self-renew long term and differentiate along multiple lineages to generate different tissues. In the embryo, multipotent stem cells respond to various cues to undergo morphogenesis and produce these tissues. The skin epithelium is an excellent model to explore how multipotent stem cells are able to respond to different signals to generate functional tissues. Stem cells are known to reside in the epidermal basal layer, where they function in homeostasis to generate the barrier that protects the body surface. Stem cells also reside in a niche of the hair follicle (HF) known as the bulge, where they function todrive the hair cycle. Remarkably, skin stem cells can be maintained and passaged long-term in culture, without losing their ability to regenerate tissues. To understand how skin stem cells and their native niches become established and maintained, we've developed methods to isolate and transcriptionally profile HF bulge and epidermal basal cells. The cells differ in cell cycling rates and gene expression. In the epidermis, basal cells are quite homeogeneous in cycling rate, which is faster than HF stem cells. Moreover, in normal HF homeostasis, stem cells remain quiescent during the resting stage of the hair cycle, which can last for weeks. During the transition to the growth phase, HF stem cells must be activated so that they can fuel the production of the differentiated cells of the growing hair. Upon injury, HF stem cells must be rapidly mobilized to repair epidermis and sebaceous glands, a feature that intriguingly appears to be more efficient in young mice. We've focused on dissecting the underlying mechanisms that regulate the fascinating differences in cycling rates of stem cells and which govern the maintenance of stem cells in their undifferentiated vs committed states. Our studies have begun to show that when sustained through genetic mutations, the pathways involved in stem cell activation lead to tumorigenesis and skin cancers.


Axel Ullrich

Max Planck Institute of Biochemistry, DE


Axel Ullrich was trained as a biochemist at the University of Tübingen (Germany) and earned a Ph.D. in Heidelberg in Molecular Genetics in 1975. After a postdoctoral tenure at the University of California, San Francisco, he joined Genentech in 1978. His work in the field of signal transduction research has elucidated major fundamental molecular mechanisms that govern the physiology of normal cells and allow insights into patho-physiological mechanisms of major human diseases such as cancer. Since 1988, he has been Director of the Department of Molecular Biology at the Max-Planck-Institute of Biochemistry in Martinsried. He is an elected member of EMBO, the German Academy of Natural Scientists "Leopoldina" and the American Academy of Arts and Sciences (AAAS). He has been a leader in genomics-based molecular medicine, translating basic science discoveries in the signal transduction field into medical applications for over 30 years. He received numerous honours and awards for his translational work which has been published in more than 500 articles in international journals and with over 80,000 citations he is one of the ten most cited scientists over the past 25 years worldwide.

Title & Synopsis
From Gene to Therapy: OncoGenomics-based cancer drug development

Cancer represents a disease prototype that is connected to defects in the cellular signaling network that controls proliferation, motility, invasivity, survival and recognition by the immune surveillance system. The first insights into the genetic basis of cancer were obtained by comparing the sequences of retroviral oncogenes with human proto-oncogenes in the early 1980ies.
For the past years we have a strategic approach which began with the cloning of the EGF receptor cDNA and the related receptor HER-2/neu and translated the animal oncogene concept into target-directed therapy of human cancer. This work yielded the first specific oncogene target-based, FDA-approved (1998) therapeutic agent, “Herceptin”, for the treatment of metastatic breast cancer. Subsequent “target-driven drug development” efforts that employed various genomic analysis strategies led to the identification of the receptor tyrosine kinases HER3, FGFR4, Axl/Ufo and Flk-1/VEGFR2 as critical signaling elements in tumor progression. The latter served, in cooperation with SUGEN Inc./Pharmacia/Pfizer, as basis for the development of SU11248. The drug discovery process that led to SU11248 represents a prototypical example for the adaptation of cancer therapeutics from highly specific to multi-targeted drugs. In 2006 the FDA approved SU11248/SUTENT/Sunitinib for the treatment of Gleevec-resistant GIST and Renal Cell Carcinoma (Pfizer) and the European Agency EMEA followed suit. Current research efforts aim at the elucidation of the mechanistic relevance of the Sunitinib target profile which may aid in the prediction of patient response to this multi-specific cancer therapeutic.


Stem Cells - Molecular Medicine Symposium

Fiona Watt

Cambridge Research Institute, Cancer Research UK


Fiona Watt has a D.Phil. from Oxford University, studying the suppression of malignancy in cell hybrids. Postdoctoral work at MIT, studying human epidermis in culture. Group leader at Kennedy Institute of Rheumatology in London, studying differentiation of epidermal cells and chondrocytes in culture, head of Laboratory at Cancer Research UK London Research Institute, studying cells in normal epidermis and in squamous cell carcinomas. In 2007 moved to Cambridge as Herchel Smith Professor of Molecular Genetics, deputy director of CRUK Cambridge Research Institute and deputy director of Wellcome Trust Centre for Stem Cell Research.


Title & Synopsis
Stem cells & tumour initiating cells in mammalian epidermis

Mammalian epidermis is maintained throughout adult life by self-renewal of stem cells and differentiation of their progeny. Different reservoirs of stem cells lie in different epidermal locations, and the type of differentiated lineages they found is regulated by local signals. Wnt signalling plays a central role in controlling the size of the stem cell compartment and regulating lineage selection. Downstream pathways involving Hedgehog, Notch and the vitamin D receptor modulate epidermal responsiveness to beta-catenin activation. It is widely believed that stem cells are the epidermal tumour initiating cells because the more differentiated cells are resident in the tissue for a relatively short time. Nevertheless, there is evidence that differentiating cells can contribute to tumour development, either directly as tumour initiating cells or indirectly by communication with stem cells and cells of the bone marrow. I will discuss the relationship between normal tissue stem cells and tumour initiating cells and some of the mechanisms by which differentiated cells contribute to tumour development.


Shinya Yamanaka

University of Kyoto,JP


Shinya Yamanaka received his M.D. from Kobe University in 1987 and his Ph.D. from Osaka City University in 1993. From 1987 to 1989 he was a resident at the National Osaka Hospital. He spent the period from 1993 to 1996 as a postdoctoral fellow in the Gladstone Institute of Cardiovascular Disease, San Francisco. He returned to Osaka City University Medical School to take an assistant professor position in 1996, and was appointed as an associate professor at Nara Institute of Science and Technology in 1999, where he became a full professor in 2003. He moved on to take up his current position as a professor in Kyoto University in 2004. In addition, he received an appointment as a visiting scientist at the Gladstone Institute in 2007. The ultimate goal of his research is to generate pluripotent stem cells directly from patients' somatic cells by using defined factors. He hypothesises that the factors that induce pluripotency also play important roles in the maintenance of pluripotency in ES cells. Based on this hypothesis, he has selected candidates for pluripotency-inducing factors. He has also developed sensitive assay systems to evaluate the candidates. By using these systems, he has demonstrated that retrovirus-mediated transfection of four transcription factors (Oct-3/4, Sox2, c-Myc, and KLF4) into mouse fibroblasts results in the generation of iPS (induced pluripotent stem) cells. He is now trying to apply this technology to human cells and overcome safety issues regarding the usage of retroviruses and c-Myc.

Title & Synopsis
Induction of pluripotency by defined factors

Human ES cells have been expected as suitable resources for cell transplantation therapies. However, it has sparked ethical controversy and causes immune rejection. Hence, we decided to generate an ideal pluripotent stem cell for innovative medicine. It first, we constructed a pluripotency assay system that the candidate factors are introduced into neonate fibroblasts via retrovirus vectors. As the result, the set of Oct3/4, Sox2, c-Myc, and Klf-4 gave rise to drug resistant colonies implying potential pluripotency. The survived cells resembled ES cells in terms of morphology and proliferation showed ES cell markers and formed teratoma. It was named as induced pluripotent stem cell (iPS cell). iPS cells were created even from adult mouse fibroblasts. Moreover, iPS cells based on Nanog-expression demonstrated germline transmission. Furthermore, we successfully generated iPS cells from human adult fibroblasts, using a modified protocol. However, tumor formation was observed in chimera mouse, probably due to c-Myc retrovirus integrated into genome. We re-modified the protocol and successfully established iPS cells without using c-Myc. As further effort to lower a risk of tumorigenesis, we recently succeeded in developing a virus-free method - using a pair of plasmid vectors, instead of retrovirus vectors, to introduce the four genes into mouse fibroblasts. Further research results are discussed from the points of safety and induction efficiency of iPS cells for future clinical grade.


Austin Smith
University of Cambridge, UK

Austin Smith, Wellcome Trust Centre for Stem Cell Research, University Of Cambridge, obtained his Ph.D. from the University of Edinburgh in 1986. Following postdoctoral research at the University of Oxford, he joined the Institute for Stem Cell Research at the University of Edinburgh (formerly Centre for Genome Research) in 1990 as a group leader. In 1996, he was appointed Director of the Centre. He was appointed MRC Research Professor in 2003. He took up the post of Director of the Wellcome Trust Centre for Stem Cell Research at the University of Cambridge in the autumn of 2006. His expertise is in the field of stem cell biology and he has pioneered key advances in the field of Embryonic Stem (ES) Cell research. His research focuses on the molecular and cellular controls of embryonic and somatic stem cells, and on interconversion between pluripotent and tissue-restricted states.

Title & Synopsis
Natural & induced pluripotency

Pluripotency may be defined as the capacity of a single cell to generate in a flexible manner all lineages of the mature organism. In other words a pluripotent cell is a cell with no predetermination. What are the design principles of this unrestricted cell state? Genetic and cell biological studies point to transcription factor command rather than epigenetic governance. Persuasive support for this view comes from the remarkable discovery of Shinya Yamanaka that pluripotency can be recreated from somatic cells through transcription factor induced reprogramming. So how is this privileged status acquired and how can it be maintained without loss of potency?


Hans Clevers
Hubrecht Institute, NL


Hans Clevers obtained his M.D. degree in 1984 and his PhD degree in 1985 from the University of Utrecht , the Netherlands . His postdoctoral work (1986-1989) was done with Cox Terhorst at the Dana-Farber Cancer Institute of the Harvard University, Boston, USA. From 1991-2002, he was Professor in Immunology at the University of Utrecht and, since 2002, Professor in Molecular Genetics. Since 2002, he is Director of the Netherlands Institute for Developmental Biology, Utrecht. He has been a member of the Royal Dutch Academy of Sciences since 2000 and is the recipient of several awards, including the Dutch Spinoza Award in 2001, the Swiss Louis-Jeantet Prize in 2004, the Memorial Sloan-Kettering Katharine Berkan Judd Award in 2005 and the Israeli Rabbi Shai Shacknai Memorial Prize in 2006.

Title & Synopsis
Lgr5 intestinal stem cells in self-renewal & cancer

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-LacZ reporter strain, lineage tracing experiments were performed in adult mice. The Lgr5+ve crypt base columnar cell (CBC) generated all epithelial lineages over a 14 month period, implying that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers. We have now established long-term culture conditions under which single crypts undergo multiple crypt fission events, whilst simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5+ve stem cells can also initiate these crypt-villus organoids. Tracing experiments indicate that the Lgr5+ve stem cell hierarchy is maintained in organoids. We conclude that intestinal crypt-villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.