Systems Biology and New Sequencing Technologies
16-18 June 2010
Barcelona, Spain

Organisers:

Draft Report

Summary

Scope: The conference focused on the parallel advances in two relatively disconnected areas of science that are boosting our understanding of biological systems. On the one hand, systems biology, with its integration of high-throughput biological data and its emphasis on quantitative modeling and simulation, is providing a global perspective of biology that goes beyond classical reductionist approaches. On the other hand, new sequencing technologies are developing at an enormous speed, and provide whole genome and transcriptomics data. These data revealed previously unexplored genomic features such as functional intergenic regions, copy number variations and other genomic differences between members of the same species, as well as excruciating details on transcriptional regulation and the large world of non coding RNA. In this meeting, we gathered an inter-disciplinary group of scientists with roots in these two disciplines with the aim to create a forum to discuss new ideas and explore what lies in overlap between these two growing fields. This meeting was also the opportunity for technology developers to present the latest machines available and explore possible applications with bench biologists. Conversely, biologists could challenge technology developers with possible applications for future technologies.

Scientific Content

Recent years have seen system biology as a means to understand biological systems’ behaviour by integrating data of various types (genome, transcriptome, proteome, metabolome, phenotypes, and other –omes), using development of data standards and bringing together bench biologists with bioinformaticians, statisticians, modelers and mathematicians. Now the explosion and availability of sequencing technologies allow one more twist in this quest by addressing functional genomics questions using the power of full genomics and transcriptomics contents (Figure 1). Our conference aimed at exposing the best results of both approaches independently and their synergistic potential when combined. The conference was structured in four sessions, Systems Biology, New Sequencing Technologies, Applications, and Perspectives. Highlights of those sessions are described below

Figure 1. Of the omics technologies that the field of Systems Biology aims to integrate,
recent disruptive newsequencing technologies have allowed for qualitative changes in
our way of thinking genomics and transcriptomics research.

Session 1: Systems biology
This session covered different aspects of large scale data analysis and integration and was centered mainly on information coming out of high throughput gene expression data, as well as ultrasequencing studies. The presentations ranged from the analysis of the bacterial transcriptome to the use of expression data to classify and predict the outcome of prostate cancer tumors. A constant of the presentations was the overwhelming amount of data that is generated and the need of finding ways of integrating that data in meaningful ways. An aspect of systems biology that was not covered was the modeling aspect of transcriptional networks obtained from dynamic sequencing data.

By integrating different data types (mostly gene expression data and ChIP-chip or ChIP-seq data), several laboratories have achieved the reconstruction of genetic networks to a level allowing the identification of novel drug targets. Along these lines, Andrea Califano (Columbia University), talked about the identification of master integrators of tumor-related phenotypes. Olga Troyanskaya (Princeton University) talked about “Understanding biology of disease based on diverse functional genomics data”. Ioannis Xenarios (Swiss Institute of Bioinformatics) presented an interesting work explaining the association of gene expression profiles with phenotypic characteristics of the hematopoietic blood lineages, which allowed mechanistic modeling the genetic networks involved in the differentiation.

 Similar approaches were applied to decode microbial regulatory networks by Luis Serrano (Center for Genomic Regulation) “Transcriptome Complexity in a Genome- Reduced Bacterium”. Our invited speaker Saeed Tavazoie (Princeton University) couldn’t come to the conference due to personal reasons. In his place Roderic Guigo (Center for Genomic Regulation) presented his talk “Uncovering and understanding splicing through massively parallel sequencing”, in which new insights on basic transcritptional mechanisms where hypothesised by careful analysis of RNAseq data.

Session 2: Sequencing Technologies
Several companies and academic institutions provided the audience with a snapshot of the state-of-the-art overview of the latest sequencing technologies. Christian Haudenschild, the Associate Director of DNA sequencing services, Illumina, Inc, discussed the many discoveries in interactions between Illumina and a number of academic collaborations in his talk “Recent advances in sequencing technologies for whole genome studies“. Ivo Gut presented the development of the Centro Nacional de Análisis Genómico (CNAG), the new sequencing center in Spain. Joe Beechem presented and interesting talk about single molecule sequencing, describing the new“Quantum-dot nanocrystal DNA polymerases” efforts at Life Technologies, Carlsbad CA USA. This technology represents a new step towards cheaper and faster sequencing and opens a window to see what is yet to come in the world of technology of sequencing. Chinappa Kodira, presented the latest application of Roche 454 Technology in Biological Discovery.

Session 3: Applications
The speakers of the following session presented a set of applications and critical perspectives on the novel technologies and systems biology approaches, from the identification of tumor stem cells to personalize medicine.

As one example of application of systems biology in the clinics, referred to as systems pathology, Carlos Cordon-Cardo (Pathology and Urology. Columbia University) showed the cell diversity within a tumor, and demonstrated the potential of single “stem-like” cell characterization in a tumorigenic tissue. Phil Kim (University of Toronto) talked about “Systematic Mapping of Multiple Specificity in Peptide Recognition Modules Using Next-Generation Sequencing”. And Robert Nutter (Life Technologies) showed the use of the SOLiDTM System to improve our Understanding of Gene Expression by RNA Sequencing. Alfonso Valencia (Spanish National Cancer Research Centre) talked about the challenges in personalised medicine. Phil Kim’s talk was a very interesting one in that it is a novel used of new sequencing technologies to probe some aspects of protein-protein interactions. In a way, the originality of the approach is an example of the possible “out of the box” applications of new sequencing technologies to biological research.

Session 4: Perspectives
The Perspectives session, was intended as a forum from where the speakers could present a critical view of the future challenges of systems biology and the opportunities being opened by the new sequencing technologies. Some of the speakers picked up on this challenge.

Jeffery Schloss (National Human Genome Research Institute, NIH) defined the near future challenges in the sequencing technologies, and suggested that as much as there is a technology push, the developers should be more susceptible to a technology pull, in which the users determine what the specifications should be for the new generation of sequencers or other new biotechnologies. Bud Mishra (New York University) presented some of the computational problems associated with the development of the sequencing technologies, in particular, how to determine the correct assembly, and open a criticism to what we called the “Reference Sequence”. Ihor Lemischka (Mount Sinai School of Medicine) talk about the challenges in stem cell research and Arnold Levine (Institute for Advanced Study) about the challenges in cancer research.

Discussion: The meeting allowed for the identification of common challenges and opportunities in the fields of Systems Biology and Next Generation Sequencing, initiating a healthy interaction between researchers in both fields. On the one hand, developers of novel sequencing technologies identified common challenges in researchers dealing with high throughput data. On the other hand, researchers got a perspective on the novel sequencing techniques and applications.

One of the goals of Systems Biology is to achieve an understanding of biological systems in a quantitative predictive manner. For this we need to have a comprehensive set of data, an integrative bioinformatics analysis and finally to model the system in a meaningful way. For instance, the transcriptome of a cell is one of the few layers of biology complexity for which we can have a comprehensive picture. Today it is possible to identify all transcripts of a sample, quantify (count) those transcripts, measure the length of the transcripts, the content of non-coding RNAs and, if desired, follow the dynamics of the transcriptome of the system. It is also possible to map all DNA binding proteins at different times of the cell cycle and in different individuals. All this information can be obtained using ultrasequencing approaches. Despite the many missing layers of biological information, like protein complexes, posttranslational modifications, chromatin structure etc…, the amount of information provided by new sequencing techniques lays a novel and powerful foundation for mathematical modeling of the transcriptome. From a Systems Biology point of view, the capability for sequencing many different species and individuals opens new vistas to the problem.

On the other hand, the developers of novel sequencing technologies need to have in mind the interests and challenges of the research community. The aim of this meeting was to nourish the synergy between the two fields to accelerate their development. Judging for the fact that 75% of the participants answer positively to the question: Should the meeting be repeated? (The remaining 25% didn’t answer), there is more room and expectation by the community that this common space between Systems Biology and New Generation Sequencing research be repeated.

Posters: A total of 30 posters were accepted at the conference, with topics ranging
from sequence assembly and analysis tools, applications of new generation
sequencing, systems biology approaches for the study of genetic diseases.

Programme

Session 1: Systems Biology
Luis Serrano, Systems Biology Program. Center for Genomic Regulation (CRG).
Barcelona, Spain: “Transcriptome Complexity in a Genome-Reduced Bacterium”
Ioannis Xenarios, Swiss-Prot group. Swiss Institute of Bioinformatics, “A dynamic
regulatory network model reveals hard-wired heterogeneity in blood stem cells”
Olga Troyanskaya, Bioinformatics and Functional Genomics. Princeton University,
“Understanding biology of disease based on diverse functional genomics data”
Andrea Califano, Biomedical Informatics. Columbia University, “Elucidating master
integrators of tumor-related phenotypes”
Roderic Guigo, Bioinformatics and Genomics Program. Center for Genomic Regulation, Uncovering and understanding splicing through massively parallel sequencing

Posters - Session 1

Session 2: Sequencing Technologies
Christian Haudenschild, Associate Director, DNA sequencing services, DNA Sequencing Business, Illumina, Inc., “Recent advances in sequencing technologies for whole genome studies“
Ivo Gut, Centro Nacional de Análisis Genómico (CNAG), “READNA - Four Generations of Nucleic Acid Analysis”
Joe Beechem, Head Single Molecule Sequencing, Genetic Systems, Life Technologies, Carlsbad CA USA. “Single molecule real-time nucleic acid sequencing-by-synthesis using Quantum-dot (Qdot®) nanocrystal DNA polymerases with FRET-based detection”
Chinappa Kodira, Genomics, 454 Life Sciences Corporation: “Applications of Roche
454 Sequencing in Biological Discovery”

Session 3: Applications
Carlos Cordon-Cardo, Pathology and Urology. Columbia University, “Systems Pathology and the Role of Risk Stratification in Treatment Selection for Patients with Cancer”
Phil Kim, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, “Systematic Mapping of Multiple Specificity in Peptide Recognition Modules Using Next-Generation Sequencing”
Robert Nutter, Life Technologies, "Using High Throughput RNA Sequencing on the SOLiDTM System to Improve our Understanding of Gene Expression".
Alfonso Valencia, Computational Systems Biology. Spanish National Cancer Research Centre: "Some of the bioinformatics challenges in a personalise medicine context"
Henk Stunnenberg, Department of Molecular Biology. Nijmegen Center for Molecular Sciences: “A systems biology approach to gain molecular insight into differentiation and transformation pathways”

Session 4: Perspectives
Jeffery Schloss, Division of Extramural Research, National Human Genome Research Institute, National Institutes of Health. USA: “Can We Make Genome Sequencing into a Routine Laboratory Experiment?”
Bud Mishra, Bioinformatics Group. Courant Institute, New York University:“Detectability of Certain Dark-Genome Contigs: Algorithms for Assembling Genomes Correctly”
Ihor Lemischka, Integrative Stem Cell Biology. Mount Sinai School of Medicine: “Pursuing Pluripotency”
Arnold Levine, The Simons Center for Systems Biology. Institute for Advanced Study: “The Evolution of the p53 Family of Genes: A Structural and Functional Analysis”