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October 15 (Mon)

◆Big Hall

<Keynote> 10:00-12:00
  Dr.Jun Wang (Beijing Genomics Institute)
  Title: Three million genomes project at BGI
  Abstract: Breathtaking progress in DNA sequencing technology has made the costs dropping and throughput increasing in a lighting speed. With more organisms including human sequenced, flood of genetic data is being generated worldwide every day. Progress in genomics has been moving incrementally due to this revolution in sequencing technology. At the same time, large scale studies in exomics, metagenomics, epigenomics, and transcriptomics all become realistic suddenly. Not only do these studies provide the knowledge to basic research, but also immediate benefits to application. Scientists across many fields are utilizing these data for the development of better crops and livestock; for diagnostics, prognostics and therapies for cancer, and other complex diseases. BGI is on the cutting edge of translating genomics research into molecular breeding and disease association studies with belief that agriculture, medicine, drug development and clinical treatment would eventually enter a new stage with the understanding of genetic components of all the organisms. We are dedicating to three projects: 1) Million Species/Varieties Genomes Project aims to sequence a Million economically and scientifically important plants/animals and model organisms, including the breeds and the varieties. The project is best represented by the newly sequenced Giant panda, potato, macaca genome, as well as many resequencing projects. 2) Million Human Genomes Project, is focusing on large scale population studies and association studies, using whole genome or whole exome sequencing strategies. 3) Million Eco-System Genomes Project aims to sequence the metagenome and cultured microbiome of all kinds of environment, including the micro-environment in the human body.
Dr. Shawn Douglas (Wyss Institute for Biologically Inspired Engineering at Harvard)
  Title: Nanoscale construction with DNA
  Abstract: The programmability of DNA makes it an attractive material for constructing intricate nanoscale shapes. One method for creating these structures is DNA origami, in which a multiple-kilobase single-stranded 'scaffold' is folded into a custom nanoscale shape by interacting with hundreds of short oligonucleotide 'staple' strands. I will talk about our efforts to realize demand-meeting applications of this method, including our recent development of nanoscale devices to mimic cell‐signaling stimulation carried out by our own immune systems.
<Invited Talks: Database and integration of information1> 14:00-15:30
Takashi Mizuma(Tokyo University of Pharmacy and Life Science)
Naomi Nagai(Pharmaceuticals and Medical Devices Agency)
  Title: In silico approach in drug development –Bridging from preclinical to clinical development, the regulatory point of view-
  Abstract: Pharmacokinetics (PK) is an applied science that quantitatively evaluates and predicts the fate of drugs in the living body. It is currently the common understanding that PK is not only utilized for proper use of drugs in the medical practice, but also an indispensable knowledge/research field in drug development for discovering new drug as well as establishing effective and safe use of drugs. The model based approach such as physiological PK or animal scale up technique, in which evidences obtained from in vitro or animal studies are extrapolated to in vivo situations, has been actively studied and lots of data and publications have been reported by academic researchers. For approval of drugs, data obtained in the step by step manner, based on the nonclinical/clinical studies, should be included in the new drug application dossier. Recently, modeling and simulation (M&S) has been actively applied as a tool in drug development, for integrating minimal requirements of PK, toxicological and pharmacological data as well as available information to predict clinical response quantitatively, making go/no-go decision from preclinical to clinical phase and/or designing appropriate clinical trials. This approach may positively contribute to establish a rational drug development management with shorter development period, higher productivity, lower cost as well as minimal use of animals. In my talk, role of M&S in recent drug development will be presented based on new drug consultation and review experiences in Japan.
Kiyohiko Sugano(Asahi Kasei Pharma)
  Title: The paradigm shift in oral absorption prediction: analysis of in vitro data and oral absorption prediction using fully-mechanistic model
  Abstract: Oral absorption simulation is anticipated to be a powerful tool to improve the efficacy of drug discovery and development. In the past, apparent in vitro parameters were directly used as input parameters for semi-empirical mechanistic models. At present, this paradigm is shifting to the way that the in vitro data is first deduced to each primary factor and then input to fully-mechanistic physiological models. This approach enabled us to connect the chemical structure all the way down to the in vivo oral absorption. In addition, it enabled the prediction of species differences, food effect, inter-individual variation, etc. In this presentation, the model equations for the processes of oral drug absorption will be introduced. The relationship between the primary factors and chemical structure and in vivo predictability will be also discussed.
Hideyoshi Harashima (Hokkaido Univ.)
  Title: Multifunctional Envelope-type Nano Device for Nanomedicine
  Abstract: Recently, we developed a multifunctional envelope-type nano device (MEND) as a novel non-viral gene delivery system based on a new packaging concept termed “Programmed Packaging”. Programmed Packaging was proposed to develop a rational non-viral gene delivery system equipped with various functional devices, including ligands for specific receptors, pH-sensitive fusogenic peptides for endosomal escape, and a nuclear localization signal (NLS) for enhanced nuclear delivery, to overcome several barriers in the process of gene delivery to the nucleus of target cells. R8-MEND can be applied for the delivery of siRNA. We succeeded to develop how to package siRNA into R8-MEND, although there is some difference in packaging method between pDNA and siRNA. Endosomal escap was enhaced by introducing GALA peptide, which is known as a pH-sensitive, membrane fusogenic peptide, in the form of cholesteryl-GALA. We have found an importance to control the number of membrane layer, since excess layers covering siRNA core in cytosol can be a rate limiting step. Di-lamellar MEND (D-MEND), which has two membrane layers can induce remarkable enhanced silencing effect in the HeLa cells stably expressing luciferase. The optimized R8/GALA-D-MEND was applied to knockdown SOCS1 gene in dendritic cells (DC) to enhance immune response. Significant antitumor effects were observed by administering DC which knocking down SOCS1 gene ex vivo. In order to apply MEND to tumor tissue via a systemic administration, it is essential to endow a long circulation property, however, PEG coating significantly inhibited transfection activities. Most of the current cleavable PEG devices have been designed to be cleaved in response to some feature of the intracellular microenvironment. Therefore, a cleavable PEG-lipid triggered in a tumor specific manner would be favorable for tumor gene delivery. To realize a tumor-specific cleavable PEG system, we focused on the enzyme, matrix metalloproteinase (MMP), which is involved in angiogenesis, invasion and metastasis of malignant tumors due to its ability to degrade the extracellular matrix. The MMP substrate peptide was inserted between the PEG and DOPE as a linker, and the resulting conjugated PEG-peptide-DOPE ternary conjugate is referred to as PPD. A PPD-MEND encapsulating siRNA with a diameter of 100-200 nm exhibited a higher in vivo gene silencing than a conventional (non-cleavable) PEG-lipid modified MEND (PEG-MEND).
<Invited Talks: Database and integration of information2> 16:00-17:30
Toru Horie (DeTher research laboratory INC)
  Title: Importance on prediction of human ADME in drug discovery process
  Abstract: Prediction of drug metabolism in human is a difficult from drug metabolism in animals,, because there is a species differences on the drug metabolism .The success of prediction of drug metabolism and pharmacokinetics in human has been obtained from ADME properties of drug metabolism in liver and small intestine of humanaized animals ,.A PXB-mouse, (a chimeric animal model with functional humanized liver, )is expected to be a useful tool to study pharmacokinetics or drug metabolisms in vivo. PXB-mice were produced by transplantation of human hepatocytes, via spleen into urokinase-type plasminogen activator-transgenic SCID mice (uPA/SCID mice), which had liver disease and were immunodeficient. The mRNA expressions of phase I (hCYPs) ,phase II enzymes and transpoters in humans in the liver were confirmed by measurement by RT-PCR. TheCYP3A-HAC was then introduced into mouse embryonic stem (ES) cells using the microcell mediated chromosome transfer technique. It is clear that a combination approaches using PXB mice and CYP3A4-HAC mice will ultimately be required to fully characterized the PK in human. The findings suggests that PXB-mice and CYP3A4-HAC mice as a human-based experimental model showed a usefully for the prediction of clinical drug interaction and human ADME. The use of both animal models could be an effective tool in the selection of drug candidates. in drug discovery process.
Yukio Tada (OCDD, the Univ. of Tokyo)
  Title: Lead optimization of compound in consideration of pharmacokinetics
  Abstract: We must consider pharmacokinetics in a lead optimization process to get a desirable drug candidate. The Biopharmaceutics Classification System (BCS) is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration (FDA). This BCS restricts the predicted absorption using aqueous solubility and permeability of compound. Frequently, the aqueous solubility is apt to decrease at the same time to have improved the biological activity by depending on lipophilicity of compound. Therefore, it is always necessary to be careful so that our compound does not belong to BCS class II (high permeability, low solubility).  Furthermore, it is important to design a low toxic compound as possible based on the physicochemical properties of compound to get a safer drug candidate. I will introduce the lead optimization of Splatast tosilate: antiallergic drug and TAS-102 (Phase III): antitumor agent in consideration of pharmacokinetics.

◆Small Hall

<Invited Talks: Database and integration of information> 14:00-15:30
Yasukazu Nakamura (NIG/SOKENDAI)
  Title: Integration of DB's for microbes and plants from the viewpoint of(meta-) genomics.
  Abstract: I will introduce two programs in the "Program for Coordination Toward Integration of Related Databases” project by the National Bioscience Database Center (NBDC), supported by the Japan Science and Technology Agency. The first is the "Integration of DB's for microbes by genomic and meta-genomic information" program which is conducted by Tokyo Institute of Technology, National Institute of Genetics and National Institute for Basic Biology. Second is the "Integration of databases for plants based on the genomic information" which is carried by Kazusa DNA Research Institute and Niigata University. These programs intend to integrate the knowledge in each research domain based on the genomic information.
Toshiaki Katayama(DBCLS)
  Title: Development of technologies for information integration in DBCLS
  Abstract: In the Database Center for Life Science (DBCLS), as denoted by the name, we are developing various technologies for the integration of life science databases. Recent expansion of the sequencing technologies brought exponential growth of the DNA database in its size, besides, another particular aspect of the biomedical databases is in their diversity. To understand the meaning of newly produced data effectively, we need to develop a new integrated infrastructure covering those heterogeneous knowledge bases. We are already providing several services supporting the accumulation, retrieval, and conversion of data. Since 2008, we started to host the BioHackathon, annual international developers’ meetings, to resolve wide range of issues in the standardization and interoperability of services and data resources. Recently, we started to apply the Semantic Web technologies for creating new database systems including the design of persistent URIs, modeling genomic or environmental information as RDF, and developing ontologies for the annotation.
Kazuhiko Fukui, Toshiyuki Tashiro, Yukimitsu Yabuki, Kiyoshi Asai(AIST)
  Title:  Integration and Federation of Bioinformatics Tools using Platform and Semantic Technologies
  Abstract: The amount of data in the field of life science has grown exponentially, owing to recent improvements of high-throughput experimental technologies. In order to use such data efficiently and effectively, computational tools need to be joined together in a coordinated system that can automatically execute a set of analyses in series or in parallel. Workflow systems are now becoming an indispensable system for addressing how to treat large-scale data and to acquire additional values on the data efficiently by integrating numerous computational tools/software. We introduce workflows for bioinformatic analytical resources which are capable of analyzing biological data easily using an eclipse based platform. The developed workflow enables users to compose a combination of analytical tools and visualize the integration of results on a platform. On this platform, users can combine independent analytical nodes from a repository of the bioinformatics tools developed at CBRC and external tools/databases by selecting them in an easy drag-and-drop manner. In addition, the analysis tools we are developing under this platform environment use SOAP and SADI (Semantic Automated Discovery and Integration) services, protocol and framework enabling communication with remote PC program and data. In order with development of RDF DB, we add a RDF input-and-output function to analysis tools using SADI framework which makes possible large-scale analysis combined with RDF DB, and are performing ontology development of analytical service.

Availability: http://togo.cbrc.jp/en_index.html
Acknowledgements: This research is carried out through participation in the Life Science Database Integration Project implemented by Japan Science and Technology Agency (JST), Japan

Susumu Goto(Kyoto Univ.)
  Title:  GenomeNet for the integration of databases and tools
  Abstract: Starting from 1992, the GenomeNet service at Kyoto University has provided DBGET database retrieval system for various molecular biology databases. We have also been developing LinkDB for the link information among databases from 1994 and KEGG database resources for understanding higher-level functions and the utilities of biological systems from 1995. Whereas DBGET/LinkDB integrates many existing databases, KEGG tries to integrate knowledge or data itself in a unified manner. In addition, DBGET/LinkDB provides a retrieval function by keywords and links in contrast with the KEGG for genome and pathway analyses. In that sense, the integration policy in DBGET/LinkDB and KEGG can be regarded as "loosely coupling" and "tightly coupling", respectively. I would like to introduce recent developments in GenomeNet by focusing on such a relationship between DBGET/LinkDB and KEGG.
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