Day 1 :
Keynote Forum
Andreas Scherer
Golden Helix Inc., USA
Keynote: Key success factors implementing precision medicine
Time : 10:00-10:45
Biography:
Andreas Scherer is the CEO of Golden Helix. He is also Managing Partner of Salto Partners, a management consulting firm headquartered in the DC metro area. He has extensive experience in managing growth as well as orchestrating complex turn-around situations. He holds a PhD in Computer Science from University of Hagen, Germany and a Master of Computer Science from University of Dortmund, Germany. He is author and co-author of over 20 international publications and has written books on project management, the internet and artificial intelligence. His latest book, “Be Fast or Be Gone”, is a prize winner in the 2012 Eric Hoffer Book Awards competition and has been named as finalist in the 2012 Next Generation India Book Awards.
Abstract:
Almost 2500 years ago, Hippocrates captured one of the key principles underlying precision medicine. In the 21st century we take the understanding of the individual characteristics of a person to a new level. By leveraging information about an individual’s genome we are able to increase the effectiveness of medical treatments. The goal is to have more successful outcomes by providing targeted therapies. The cost of sequencing a genome has dramatically dropped since the first draft of the human genome sequence was published in 2001. This is a key enabler. Now, it is very much in reach for a wide range of patients to receive a gene panel analysis or even a whole exome/genome analysis. But there is more that is required. Through a collaborative effort between clinicians, pharma companies, scientists and regulatory agencies we are working on a new framework for standard care on a global basis. This talk will discuss the components that will facilitate the power of precision medicine. Now, the concept of Precision Medicine is not new. Medical practice has always been about treating each individual patient. Clinicians are very familiar with the fact that different patients respond differently to specific treatments. What is new is that the advances in the field of genomics offer a new ways to develop targeted therapies, diagnose patients and predict who will respond favorably from those targeted therapies. Since the approval of Kalydeco (ivacaftor) on January 31, 2012 by the FDA to help cystic fibrosis patients with G551D mutation, the FDA has approved a number of so called targeted therapies primarily in the cancer space: crizotinib, vemaurafinib, dabrafenib and treminib – each have been approved for use in patients with a particular tumor profile. Precision Medicine is well on its way. This generation experiences a paradigm shift in medicine. Clinicians, empowered by state of the art bioinformatics pipelines can make better informed and more targeted decisions. Patients benefit from individualized treatment plans and better clinical outcomes. There is still a lot to do.
Keynote Forum
Hans Lehrach
Max Planck Institute for Molecular Genetics, Germany
Keynote: Virtualized drug development for (truly) personalized drug therapy
Time : 10:45-11:30
Biography:
Hans Lehrach has obtained his PhD at the Max Planck Institute for Experimental Medicine and the MPI for Biophysical Chemistry in 1974. He has then moved on to Harvard University, Boston (1974-1978) and became Group Leader at EMBL, Heidelberg (1978-1987). He then moved to the Imperial Cancer Research Fund, London (1987-1994) to become Head of the Genome Analysis Department. In 1994 he has returned to Germany to become Director at the MPI for Molecular Genetics (1994-2014). He has founded several biotechnology companies such as Sequana Therapeutics, GPC Biotech, Scienion, Prot@gen, PSF Biotech and Atlas Biolabs. He is the Founder of the Berlin-based company Alacris Theranostics GmbH, specializing in the development of new approaches for personalized medicine for cancer patient diagnosis, treatment and drug stratification. In 2010 he founded the non-for-profit research institute Dahlem Centre for Genome Research and Medical Systems Biology.
Abstract:
Every patient is different. In particular, every tumor is different. Even subgroups of tumor cells can react differently to specific therapies, due to the heterogeneity of many tumors. Drug therapies therefore typically only help a fraction of patients; many patients do not respond with some suffering sometimes severe side effects of ineffective treatments. The ability to identify effects and possible side effects of different drugs on individual patients will, in our view, require highly detailed molecular analyses of every individual patient and his/her individual disease; data that is integral to generating individualized computer models, which can then be used to test the effects of drugs (or other therapies) on the individual. This will, on one hand, provide a basis for a truly personalized selection of therapies optimal for the individual patient, first in cancer patients but increasingly also in other areas of medicine and prevention. It will, however, also open the way to an increasing virtualization of the drug development process, by e.g., virtual clinical trials of drug candidates carried out throughout the development process.
- Genome Medicine| Future trends in Genomics| Biomarkers & Molecular Markers |Bioinformatics in Genomics| Plant Genomics | Pharmacogenomics & Personalized Medicine| Cancer Genomics
Chair
Gerald J Wyckoff
University of Missouri-Kansas City, USA
Co-Chair
Yuri E Dubrova
University of Leicester, UK
Session Introduction
Gerald J Wyckoff
University of Missouri-Kansas City, USA
Title: The next generation of genomicists
Time : 11:45-12:15
Biography:
Gerald J Wyckoff is currently focusing on how evolutionary knowledge can factor into drug discovery. He has been creating and deploying new algorithms for better handling the targets of new chemical entities. His lab deals with aspects of Bioinformatics drug development and study of evolutionary processes at the molecular level.
Abstract:
The past challenges of genomics inform the future issues that will confront the “next generation” of genomicists and we need to examine some of the mistakes of the past to not repeat those mistakes in the future. Clear issues revolve around failing to plan for future disruptive technologies, trying to fix problems of the “last generation” of genomics, inadequate data collection and annotation that will lead to loss of data or unusable data and a failure of collaboration among labs collecting genomics data or setting up biobanks and repositories. These issues are training issues as much as they are scientific ones, so we need to look at how to set up our curriculums to adequately prepare students not just for the jobs they will want immediately but for those careers they want to have in twenty years. Considering how training takes place now, this might mean disrupting our own modes of teaching and relying more on online learning and MOOCs as opposed to the “apprentice-like” system that is generally in place, particularly for MS and PhD students. Exposing those students to the cutting-edge problems being encountered by institutions trying to solve immediate problems will prepare them for encountering new, novel issues across their careers but might draw attention away from focusing on immediate problems that are generally the focus of many MS and PhD theses. We will present a series of potential problems and discuss some potential modes for solving the training and technical issues that they pose.
Yuri E Dubrova
University of Leicester, UK
Title: A genome-wide analysis of mutation induction in the mouse germ-line
Time : 12:15-12:45
Biography:
Yuri E Dubrova has completed his PhD from NI Vavilov Institute of General Genetics, Moscow. He is a Professor of Genetics at the Department of Genetics, University of Leicester. He has published more than 90 papers in reputed journals and has been serving as an Editorial Board Member of Mutation Research.
Abstract:
The ability to predict the genetic consequences for humans of exposure to ionizing radiation and chemical mutagens has been one of the most important goals of human genetics in the past fifty years. However, despite numerous efforts, little is known about the genetic effects of radiation exposure in humans and the only definitive evidence for germ-line mutation induction in vivo in mammals comes from mouse studies. Recent advances in genetic technologies have provided new microarray-based and next generation sequencing-based tools for the genome-wide analysis of genetic variation, which have the potential for characterizing germ-line mutation in humans and mice. Using microarray-based comparative genomic hybridization and high depth (>22X) whole genome HiSeq sequencing we have recently carried out a matched case control experiment to investigate the effects of ionizing radiation on germ-line mutation in mice. We found that the frequency of de novo Copy Number Variants (CNVs) and insertion/deletion events indels was significantly elevated in offspring of exposed fathers. We also showed that the spectrum of induced de novo SNVs is strikingly different; with clustered mutations being significantly over-represented in the offspring of irradiated males. Our study highlights the specific classes of radiation-induced DNA lesions that evade repair and result in germ-line mutation and paves the way for similarly comprehensive characterizations of other germ-line mutagens.
Tamara Raschka
Fraunhofer Institute for Algorithms and Scientific Computing, Germany
Title: Analytical strategy to unravel novel candidates from Alzheimer's disease gene regulatory networks using public transcriptomic studies
Time : 12:45-13:15
Biography:
Tamara Raschka has received her Bachelor's degree from University of Applied Science Koblenz in 2015 and she is currently pursuing Masters in Applied Mathematics, Koblenz. She has joined Fraunhofer SCAI, Department of Bioinformatics as a student in March 2015. Her research work mainly focuses on building robust approaches for analyzing public gene expression studies to explore novel and previously unknown biomarkers in a defined disease context. Currently, she is involved in publicly funded IMI project AETIONOMY where the goal is to build a mechanism based taxonomy aiding in classification of disease sub groups for patient stratification.
Abstract:
Alzheimer's disease (AD) is the most common type of dementia, progressively destroying cognitive capabilities. Despite recent progress, there are no available curable drugs; questioning our current knowledge of AD pathology. Gene regulatory networks (GRNs), generated from meta-analysis of existing studies, could help us revisit our mechanistic understanding. However, they do not elaborate on the context specificity and additionally, miss out on lesser studied genes given the tendency to focus on differential expressed genes and prior knowledge. In this poster, we present a novel strategy to determine common mechanistic patterns across all publicly available AD gene expression datasets. An optimized method of BC3Net and WGCNA were used to get robust and coherent gene regulatory patterns. This approach leverages the power of literature and iterative functional enrichment approach (derived from the data) to define context specificity. The results show significant enrichment for pathways across disparate datasets that are involved in key signaling mechanisms, like neurotrophin and calcium signaling. Interestingly, there are no common genes involved in these pathways across datasets. Among these, genetic variant and linkage disequilibrium analysis prioritized novel candidate genes, which are less studied in AD, but prominent in AD comorbidity. Some of these genes encode for cytokines, which are part of the immune response, responsible for the cell growth and differentiation and inflammation. For the first time we show that functional enrichment to generate GRNs in neurodegeneration reveal unknown yet novel biomarkers. This may lead the way to mitigate the black-box pathogenesis of AD.
Alex Lucas Hanusch
Universidade Federal de Goiás, Brazil
Title: Genotoxicity and cytotoxicity evaluation of the neolignan analogue 2-(4-Nitrophenoxy)-1-phenylethanone and its Protective effect against DNA damage
Time : 14:00-14:30
Biography:
Alex Lucas Hanusch has completed his MSc from Universidade Federal de Goias (UFG), Brazil. He is a Cytopathologist of Hospital das Clinicas, UFG, Brazil. He has published three papers and 45 abstracts to his credit.
Abstract:
Neolignans are secondary metabolites found in various groups of Angiosperms. They belong to a class of natural compounds with great diversity of chemical structures and pharmacological activities. These compounds are formed by linking two phenylpropanoid units. Several compounds that have ability to prevent genetic damage have been isolated from plants and can be used to prevent or delay the development of tumor cells. Genetic toxicology evaluation is widely used in risk assessment of new drugs in preclinical screening tests. In this study, we evaluated the genotoxicity and cytotoxicity of the neolignan analogue 2-(4-nitrophenoxy)-1-phenylethanone (4NF) and its protective effect against DNA damage using the mouse bone marrow micronucleus test and the comet assay in mouse peripheral blood. Our results showed that this neolignan analogue had no genotoxic activity and was able to reduce induced damage both in mouse bone marrow and peripheral blood. Although the neolignan analogue 4NF was cytotoxic, it reduced cyclophosphamide-induced cytotoxicity. In conclusion, it showed no genotoxic action but exhibited cytotoxic, antigenotoxic and anticytotoxic activities.
Agnieszka Zmienko
Poznan University of Technology, Poland
Title: Multiallelic copy number variations of MSH2-AT3G18530-AT3G18535 genes in Arabidopsis thaliana: In-depth analysis of genotypes, mechanisms leading to their formation and the functional implications
Time : 14:30-15:00
Biography:
Agnieszka Zmienko has completed her PhD in 2006. She works as a Research Scientist in the Institute of Bioorganic Chemistry, Polish Academy of Sciences and as an Assistant Professor in the Institute of Computing Science of Poznan University of Technology. She is a team Member of the ECBiG Regional Center which provides facilities, tools and databases for multi-level studies of biological systems. She has focused on plant genomics and transcriptomics and co-authored 15 papers in this field.
Abstract:
Copy number variations (CNVs) are intraspecies duplications/deletions of large DNA segments (>1 kb). Because of the ability to alter the gene structure or copy number CNVs may influence gene expression and by the dosage effect, the interaction of gene products within the protein and metabolic networks. Such alterations may have no phenotypic effect, but often they account for adaptive or maladaptive traits and contribute to genome evolution or phenotypic variation. We adopted two experimental techniques, multiplex ligation-dependent probe amplification and droplet digital PCR to measure the copy number of specific sequences in Arabidopsis thaliana. With those approaches we performed an in-depth analysis of a complex multiallelic CNV encompassing 3 neighboring genes (MSH2, AT3G18530 and AT3G18535). We evaluated the gene copy numbers in a large population of 189 A. thaliana ecotypes and analyzed the CNV breakpoints and the flanking regions. Based on the sequence data and eco-geographical distribution of AT3G18530-AT3G18535 deletion and duplication genotypes we created a model of non-allelic homologous recombination (NAHR) mediated by low copy repeats flanking the two genes. We propose that the observed dupl-2 and del-2 genotypes originate from reciprocal products of interchromatidial/interchromosomal NAHR. Furthermore, we performed gene expression studies to evaluate the possible consequences of CNV on the evolution and functionality of MSH2, AT3G18530 and AT3G18535 genes. In light of those data, the perspectives of utilizing natural CNV phenomenon for functional gene analysis will be discussed.
Giridharan Periyasamy
Genome Institute of Singapore, Singapore
Title: Patient derived micro tumor systems: Future trends towards improved testing systems, Realizing the potential of HTS/HCS towards precision medicine
Time : 15:00-15:30
Biography:
Giridharan Periyasamy studied at Centre for Biotechnology at Anna University, India where he obtained his PhD in Biotechnology. He is the Head of Centre for High Throughput Phenomics (CHiP-GIS) at the Genome Institute of Singapore. His research focus is on the cancer biology, drug resistance and signaling pathway networks of human diseases. Prior to his current position, he has worked as a Scientific Director of HTS/HCS Screening Core Facility at C-CAMP, NCBS, India and a Group Leader at Piramal Life Sciences Ltd., in Mumbai, India. He has more than 15 significant publications and 8 patents to his credit.
Abstract:
With increasing breadth and depth of genomics studies across a range of cancers, it is now apparent that there exists significant inter and intra-tumoral heterogeneity, with complex genotypes comprising of multiple co-existing genetic and epigenetic alterations. Current efforts are at genomic characterization of individual cancers however, has several limitations: A significant proportion of patients invariably develop resistance to current targeted therapies, for which the mechanisms are not fully unraveled and there remain a lack of treatment options. In this project, we plan to propagate patient derived cell lines in order to allow functional studies that may expand therapeutic opportunities beyond genomic-based markers. Functional studies comprise both chemical and genetic tools that perturb the signaling networks in the primary cell cultures, in order to unravel complex signaling networks that interact through crosstalk and feedback loops, which modify therapeutic vulnerability. Such screens can therefore provide insights into mediators of resistance and sensitivities, yielding predictive biomarkers as well as novel drug combinations to circumvent drug resistance. Two crucial components include an efficient scalable system to explore therapeutic combinations and the development of representative preclinical models: Patient-derived cells in 3D culture models reflect an integration of genetic, epigenetic and environmental influences and may closely mimic the chemotherapeutic (or pathway specific inhibitor)-response of the actual tumor in patients. Thus we aim to exploit the relevance and scalability of patient-derived cell lines to perform HTS/HCS based screens.
Ebtesam Al-Ali
Kuwait Institute for Scientific Research, Kuwait
Title: Phylogenetic analysis of TYLCV on tomato plants in Kuwait
Time : 15:45-16:15
Biography:
Ebtesam Al-Ali has obtained her BSc in 1993 from Kuwait University, worked for Kuwait University as Research Assistant, then joined KISR in 1993 and led 5 projects. She has published more than 5 papers in reputed journals and international conferences. Her field of experience, in plant virus detection, primer design, cloning and sequencing, ELISA, DNA Extraction, PCR Amplification, RCA Rolling Circle Amplification, TYLCV detection on tomatoes, also trained twice in the University of Wisconsin Madison under the supervision of Prof. Amy Charkowski as well as at the University of Washington state under supervision of Pro. Hanu Pappu.
Abstract:
Viral diseases of plants are widespread and cause significant economic losses in many crops. A survey of tomato viral diseases in Kuwait was conducted, the high economic losses of tomato crops induced by whitefly emerged a rapid action for identification and molecular characterization of the virus species in order to recommend appropriate control strategies. Tomato Yellow Leaf Curl Virus (TYLCL) was reported as a major pest of tomato. TYLCV isolated from severely diseased tomatoes collected over a two-year period in the main tomato growing area of Kuwait (Abdaly North) was characterized at the molecular level and the complete genomic sequence was determined. Based on the genome structure and organization and phylogenetic analysis, the Begomovirus was found to be a strain of TYLCV. One isolate that was characterized in this study had 97% and 95% nucleotide sequence identity with previously characterized Kuwaiti isolate, TYLCV-KISR and the highest sequence identity (95%) was with that of TYLCV-Almeria (Spain) isolate. Phylogenetic analysis showed that the Kuwait isolate could be a novel variant of TYLCV and suggested to be in a different lineage from known TYLCV sequences.
Martin Falk
DNA repair in head and neck cancers and their radiosensitivity
Title: DNA repair in head and neck cancers and their radiosensitivity
Time : 16:15-16:45
Biography:
Martin Falk is the Head of the Department of Cell Biology and Radiobiology at the Institute of Biophysics, Czech Academy of Sciences, Brno, CR. He has completed his PhD in Molecular Biology and Genetics from Masaryk University Brno, CR, in 2004. He has published over 30 papers with about 500 citations, given 26 invited lectures at international conferences and has been serving as an Editorial Board Member of several reputed journals. In 2009, he has been awarded the Premium of Otto Wichterle devoted by the Czech Academy of Sciences to outstanding young scientists. His research interests include radiobiology and cancer biology.
Abstract:
Head and neck (H & N) tumors are aggressive neoplasms located close to vital tissues. This makes their surgical removal often very risky and mutilating. Non surgical approaches as chemotherapy and radiotherapy are therefore preferable but only about 50% of H & N tumors respond to this conservative treatment. Unfortunately, we still miss a tool allowing for pre therapeutic selection of H & N cancer patients who will benefit from conservative therapy or primary surgery. Blind application of radiotherapy is risky since the rescue surgery (if radiotherapy fails) and consecutive patients' recovery is complicated by radiation damage caused to normal tumor surrounding tissue. Clinicians thus permanently face to a serious 'First-Therapy Dilemma'. The purpose of our work is to better understand the heterogeneity of H &N tumors in terms of their response to different ionizing radiations (gamma rays, protons and accelerated ions), reveal molecular causes of their radiosensitivity/radioresistance and potentially find a biomarker predicting these characteristics. For the first time in this context, we prepared primocultures of several different cell types (normal fibroblasts, tumor associated fibroblasts and tumor cells per se) from patients' tumors, characterized their basic molecular genetics features and compared their survival and DNA double strand break (DSB) capacity after gamma ray and proton irradiation, respectively.
Maria C Ovejero-Benito
Instituto de Investigación Sanitaria la Princesa, Spain
Title: Analysis of DNA methylation of psoriasis patients treated with anti-TNF drugs using bioinformatics tools
Time : 16:45-17:15
Biography:
Maria C Ovejero-Benito has completed her PhD in 2013 from the Universidad Autonoma de Madrid. Since 2004, she is collaborated in cutting edge projects in areas of cancer, chemistry, neurodegeneration, neurogenesis and epigenetics. She has performed research in institutions such as Cajal Institute, NYU, Universidad de Valencia, LGC, UK and the Spanish Research Council. Her scientific results have been recognized by 6 publications in high-impact factor journals and through 3 presentations and 6 posters in scientific meetings. Currently she carries out projects in Pharmacogenetics in Dr. Abad Lab in Instituto de Investigación Sanitaria la Princesa.
Abstract:
Psoriasis is a chronic, autoimmune and inflammatory skin disorder related to a combination of genetic, environmental and immune factors that affects to 1.3-2.2% of the world population. This strongly disabling disease interferes with patients’ daily life and presents a wide range of comorbidities such as cardiovascular diseases, cancer and depression that can decrease the life expectancy of psoriasis patients. Anti-TNF drugs have been the main biologic drug to treat moderate-to-severe psoriasis so far and its effectiveness can reach 80%. However, the clinical response to the administration of these drugs varies depending on the genetic and the environment of the patient. To understand this phenomenon, analyses of DNA methylation of patients treated with anti-TNF drugs were performed. Blood samples were collected from 72 patients who suffered from moderate to severe psoriasis. DNA extracted from these samples was treated with sodium bisulfite, amplified, labeled, hybridized to methylated and unmethylated probes and microarray scanning platform in HiScanSQ Illumina Inc. HumanMethylation450 BeadChips technology was used as it allows the simultaneous analysis of 485,000 individual CpGs sites. After analyzing the results with bioinformatic tools such as Genome Studio, Circos and R version 3.1.2, significative differences in the degree of methylation of several CpG islands were found. These islands regulate the expression of genes that have not been involved so far in the pathology of psoriasis. These results are very promising because they help to seed light to the mechanisms involved in this disease and path the way to find new drugs to treat psoriasis.
Sara Teresinha Olalla Saad
State University of Campinas, Brazil
Title: Screening of genetic variants in familial case of myeloid neoplasm using exome sequencing
Time : 17:15-17:45
Biography:
Sara Teresinha Olalla Saad is a Member of the Editorial Board of the Brazilian Journal of Medical and Biological Research and Referee for the journals: International Archives of Internal Medicine and Clinical and Laboratory Hematology. Her research interests include functional investigation and characterization of the involvement of new target genes and new therapies for the treatment of myelodysplasic syndromes and in leukemic lineages, clinical and molecular investigation of chronic anemias, including hereditary anemias such as sickle cell disease, deficiency of pyruvate kinase and glucose-6-phosphate dehydrogenase, spherocytosis and elliptocytosis, among others.
Abstract:
The introduction of the next-generation sequencing technologies on the research of myeloid neoplasms has provided valuable contributions on the identification of new molecular biomarkers, more accurate risk ratings and more assertive treatments. This study aimed to identify through exome sequencing specific genetic variants in a family with two sisters (39 and 40) with primary myelofibrosis and history of longtime exposure to pesticides DDT-type. To investigate the genetic variants in these patients, we proceeded to the whole-exome sequencing of DNA samples from bone marrow CD34+ hematopoietic stem cells and germline cells from peripheral blood (CD3+ lymphocytes). The samples were sequenced on HiSeq 2500 (Illumina, Inc.), strict mode and the bioinformatics analysis was conducted with the following tools, respectively: NGSQC Toolkit, BWA-backtrack, SAM tools, GATK and ANNOVAR. A set of 110 genes implicated on the pathogenesis of myeloid neoplasms has been selected for the variants filtering. The variants were considered as possibly associated to these neoplasms when they have fulfilled these criteria: Located in exonic regions, coverage values ≥30X and global minor allele frequency <1%, predicted as deleterious by SIFT software and predicted as pathogenic by PolyPhen2 tool. The filtering has identified the GATA1 Thr263Met in the bone marrow (BM) and peripheral blood (PB) of both patients and the JAK3 Val718Leu in the BM of the younger sister. The change in GATA1 is located at highly conserved region of the protein and contains no record in databases of variants to date. Besides, three variants in genes encoding drug-metabolizing enzymes were identified in one or another patient: CYP3A5 Gly31fs, CYP2A6 Ser467Stop and CYP2B6 Thr67Met.