Research and Scientific Services

The programme’s scientific highlights in 2018 included the development of Pergola, a tool to visualise and analyse longitudinal data that uses the logical infrastructure built to display annotations along genome sequences; the investigation of the impact of the death of the organism in the transcriptional patterns in tissues and the corresponding development of a forensic tool to predict the time since death based on the gene expression values in a few selected tissues; the uncovering of evidence for the existence of an active sexual cycle in Candida glabrata, an opportunistic fungal pathogen, and the discovery of a number of proteins that regulate the expression of alpha-synuclein, which is linked to Parkinson’s disease, through interactions with its 3’ UTR.

Our programme also led the “Saca La Lengua” (“Stick Out your Tongue”) citizen’s science project (https://www.sacalalengua.org/stick-out-your-tongue/). The project aims to study the mouth’s microbiome and its possible relationship with our environmental characteristics and lifestyle.
Several groups in the programme are participating in a number of large-scale genomic projects, such as ENCODE, GTEx, PanCancer, I5K, F1K, WebOfLife, IASIS, the Human Cell Atlas and others.

The programme has continued to deploy and support the European Genome-phenome Archive (EGA) in collaboration with the European Bioinformatics Institute (EBI). EGA is an ELIXIR Core Data Resource and an ELIXIR Recommended Deposition Database. It is one of the Global Alliance for Genomics and Health (GA4GH) Driver Projects. EGA is also one of the European Open Science Cloud (EOSC) Science pilot demonstrators.

The mission of the scientists in the Cell and Developmental Biology programme is to reveal the mechanisms of cell compartmentation, division and tissue organization. The department is staffed by Vivek Malhotra (mechanism of protein secretion), Isabelle Vernos (microtubule and spindle dynamics), Jerome Solon (tissue organization), Sebastian Maurer (cytoplasmic RNA localization), Verena Ruprecht (cell and tissue dynamics) and Elvan Boke (oocyte biology and cellular dormancy). Our former colleague Manuel Mendoza was recruited as a group leader to IGBMC, Strasbourg in 2017. Thomas Surrey, senior group leader from the Francis Crick Institute in London, is a leading figure in the mechanism of microtubule and spindle dynamics, who will join the CRG in October 2019. 

A large number of outstanding papers were published by members of our department, although one in particular merits special note. This paper by Jerome Solon laboratory, Sumi et al. Dev Cell (2018), describes how the cytoskeleton and the removal of specific proteins from the cell junctions control tissue organization. These findings could help to understand how animals control a tissue’s size, shape and the physiology of a tissue.

Vivek Malhotra is a fellow of the American Society for Cell Biology. Elvan Boke is funded by a European Research Council (ERC) Starting Grant. Isabelle Vernos is a member of the Scientific Council of the European Research Council (ERC) and chairs its Gender Balance Committee. 

In 2018, we welcomed Eva Novoa and her group, coming from the Garvan Institute of Medical Research in Sydney, Australia. Eva’s group studies the mechanisms and functions of the epitranscriptome, a large set of distinct chemical modifications that can be present in and regulate the function of RNA molecules.  

Some highlights of this year’s research include collaborative work involving up to five of the groups in the programme, revealing the roles of enhancer demethylation and of chromatin architecture in regulating cell fate decisions during cell reprogramming. The effects of genome conformation on transcription factor trafficking and of promoter bivalency in favouring the open genome architecture of stem cells constituted other exciting insights. Advances in RNA-based regulation include a role for Dicer-2 in mRNA activation by cytoplasmic polyadenylation and a patent application for the potential use of splicing-modifying antisense oligonucleotides in cancer therapeutics.  Another important finding was the role of DYRK1A kinase in controlling the angiogenic responses of endothelial cells. Evidence of the mobilisation of endogenous bone-marrow cells to mouse retina to induce cell fusion-mediated reprogramming of Müller glia cells can pave the way for novel retinal degeneration therapies. 

The CRG Systems Biology Programme is a leading centre in Europe for quantitative biology. The programme’s goal has always been to hire group leaders using a quantitative approach to fundamental biological problems rather than to target particular topics. The programme has therefore covered a broad range of questions: from genetics and dynamic gene regulatory networks to systems neuroscience. However, this diversity is underpinned by the common goal of combining systematic and quantitative data collection with computational models to acquire a deeper understanding of complex biological processes. Indeed, one of the programme’s key characteristics is integration between computational and experimental approaches within the same labs and in which, somewhat unusually, all of the group leaders recruited are researchers who mixed wet and dry approaches when they were postdocs.  

The programme was reviewed by the CRG SAB and an international panel in 2018, with the panel concluding that:  ‘The Systems Biology programme has been an outstanding success in every regard, numerous high-quality publications were produced and it was highly successful in attracting external grant income from blue chip funding sources. The Panel applauded the manner in which all of the individual research programmes had so seamlessly combined wet and dry lab approaches, which is key to the success of quantitative biology projects. In broader terms, public outreach and the engagement and development of translational and commercial activities within the programme was exemplary. Furthermore, the Systems Biology Programme has served as a focus for a broader community, bringing together a number of non-CRG groups from inside the building, as reflected in an extensive portfolio of joint publications.’  

We celebrate and congratulate all the group leaders and members of the programme for their achievements which have resulted in this extremely positive evaluation of the programme. 

Finally, in 2019, Arnau Sebé-Pedrós will be joining the programme as a new junior group leader. Arnau was most recently a postdoctoral fellow at the Weizmann Institute in Israel. Arnau’s lab will use single-cell genomics methods to study the origins and evolution of cell types. Welcome, Arnau! 

The core facilities programme currently comprises seven Core Facility Units: Genomics, Proteomics, Advanced Light Microscopy, Biomolecular Screening & Protein Technologies, Flow Cytometry, Bioinformatics and the Tissue Engineering Unit. The programme also includes the Histology Service and the Storage and Computing Unit that are only accessible to PRBB users or internal users, respectively.  

All of the units work towards implementing new technologies and applications in response to both our user needs and future directions in their respective fields. The most prominent new technologies set up in 2018 include: 

• Mass spectrometric application for the characterisation of protein–protein interactions and protein structural determination using chemical crosslinkers followed by LC–MS 
• Identification and isolation of extracellular vesicles by flow cytometry for the study of vesicles’ cargo 
• CRISPR/Cas9 Gene editing directly in embryos  
• PiggyBac transposon in mouse ES cells 
• CRISPR/Cas9 Gene editing in human ES cells  
• Derivation and culture of intestine organoids 
• Generation and production of in-house Cas9 enzyme tagged with fluorescence 
• NextFlow pipeline development for major workflows, community sharing and contribution to community development 

In order to establish an integrated request management solution across all core facilities, we are working closely with the developers of the software Agendo to customise it and offer an integrated solution to all our users. Agendo will manage all bookings and requests across facilities, will become the communication channel and will offer tracking of samples and projects to our users. 

In 2018, the Proteomics facility was acknowledged as a new node of the Scientific and Technological Singular (ICTS in Spanish), called Infrastructure for OMICS technologies (IOT), also comprised of the CNAG (Centro Nacional de Análisis Genómico) and the COS (Centre for OMICS Sciences) in Reus. 

The CRG core facilities are not only well-established locally, with users coming from different institutions in Spain and abroad, but we are also acknowledged partners in European initiatives. The Proteomics facility is a partner in the recently-granted INFRAIA (H2020) consortium EPIC-XS. The Advanced Light Microscopy Unit is a partner in the ESFRI initiative EuroBioimaging (EuBI), and its head, Timo Zimmerman, is the national coordinator for biological imaging. The Genomics and Proteomics Units are members of MERIL, the European Research Infrastructure portal listing facilities with more-than-national relevance (CRG being the only Spanish Proteomics Facility).  

The Core Facilities are member of the Core Facilities Excellence Alliance “Core for Life” (www.coreforlife.eu), which also includes EMBL (Heidelberg, Germany), VIB (Ghent/Leuven, Belgium), MPI-CBG (Dresden, Germany), VBCF (Vienna, Austria), the FGCZ (Zurich, Switzerland), and the Institut Pasteur and Institut Curie (Paris, France). Core for Life aims at sharing and consolidating procedures, uniting efforts in personnel training and technology validation and sharing access to facilities across institutes.  

In 2018, we refined our strategic priorities into five topics: Cancer, Rare Diseases, Personalised Medicine, Single-cell Analysis and the Genome in Action (epigenetics). High-throughput nucleic acid sequencing and data analysis are key to these topics. Our portfolio of sequencers has been diversified and extended by an Illumina NovaSeq6000, a 10x Genomics Chromium Controller, an Oxford Nanopore GridIon and ancillary instrumentation that all permit the streamlining of biological materials for sequencing. Instruments are now deployed according to the needs of the users of the CNAG-CRG Sequencing Unit and the CRG Genomics Unit. This guarantees sufficient capacity for all applications at both sites. We were renewed as an ICTS (Infraestructuras Científicas y Técnicas Singulares) and as of January 2019 this will include the CRG Genomics Unit and the CRG/UPF Proteomics Unit. Besides the re-certification and re-accreditation of ISO9001 and ISO17025, CNAG-CRG has become a BBMRI-Expert Center. Linking to biobanks across Europe facilitates academic and industrial research. 

The EU-funded RD-Connect project that enabled us to establish the RD-Connect Genome-Phenome Analysis Platform (RD-Connect GPAP) ended in 2018. When the former scientific coordinator of RD-Connect, Hanns Lochmüller, moved, we took over the scientific leadership of this project for the final year and brought the project to a successful conclusion at the end of the year. The RD-Connect Genome-Phenome Analysis Platform is now an IRDiRC Recognized Resource, it is a key tool for the EU-funded Solve-RD project and is an important part in the upcoming European Joint Project on Rare Diseases (EJP-RD), due to commence in early 2019. The RD-Connect GPAP currently holds more than 4,000 patient entries and is used by more than 600 clinicians and researchers. In order to keep up the momentum generated by RD-Connect, we established the RD-Connect Community, which aims to maintain the connection between rare disease researchers and patients. The RD-Connect GPAP also lies at the heart of the two projects funded by the Catalan Ministry of Health (PERIS), URDCat and MedPerCan, that extend its utility to capture electronic health records and integrate genomic data from cancer patients. 

CNAG-CRG researchers were also incredibly successful this year in attracting new funding, such as an ERC Synergy Project (BCLL@tlas) and several EU Horizon2020 projects (EUCanCan, which builds on the work of the ICGC-CLL project and EJP-RD). Our single-cell genomics activity brought funding from the Chan-Zuckerberg Initiative to partner up with the Human Cell Atlas project. We are taking on international leadership in genome analysis through the EU-funded EASI-Genomics Infrastructure Project, which we will be coordinating. Apart from many infrastructure activities that will be possible through this project, we will be able to establish the international standardisation of methods in genomics. Our first Innovative Medicines Initiative (IMI) project, focussed on immunotherapy for cancer, will commence in 2019. IMI projects are collaborative projects between academia and industry. A new Marie Skłodowska-Curie European Training Network, ChromDesign, will support PhD students working on nuclear structure projects. The European Commission is also supporting a Coordination and Support Action for LifeTime for the preparation of a Future and Emerging Technologies Flagship Project. 

The development of computational tools for different types of analyses of genomic data are an important part of our activity. This year we released several new computational tools, namely GEM-BS, which was adopted as the standard pipeline for DNA methylation analysis by the International Human Epigenome Consortium, BigScale for single-cell analysis, and TADbit and TADkit, tools for analysing nuclear conformation. 

Personalised medicine is a hot topic, and genomics has a major part to play in it. An EU member state initiative to share more that 1 million human genomes together with phenotype and clinical data across Europe in an interoperable and federated manner was launched in 2018. Several of our initiatives are putting us in an excellent position to play a major role in this project: the NAGEN1000, a pilot project funded by the Servicio Navarro de Salud-Osasunbidea, and the two Catalan PERIS projects, MedPerCan and URDCat, on the integration of genomic information into the clinical system. These projects put us on a solid path towards the fully-fledged implementation of personalised medicine and will allow us to play a key role in the medicine of the future. 

The EGA is a service for the permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects. The data at EGA were compiled from people whose consent agreements authorise data release only for specific research use or to bona fide researchers. Strict protocols govern how information is managed, stored and distributed by the EGA project. 

Since its launch, researchers from around the world have deposited and accessed different types of data from more than 1,700 studies in the EGA. These studies vary from large-scale array-based genotyping experiments on thousands of samples in case-control designs or population-based studies to sequencing-based studies designed to understand changes in the genome, transcriptome or epigenome in both normal tissue and in various diseases such as cancer. As a result, the EGA has grown from about 50 TB to 5,800 TB over the last six years.