Editorial

Bernard Mulligan

Europe has a very strong track record in basic research in the life sciences. In the “post-genomic era”, the character and needs of basic research in the life sciences are changing dramatically: it has become very multidisciplinary, the amount of data is increasing exponentially and huge investments in facilities are required.

The European life sciences community’s interest in policy developments in funding basic research has focused on a number of issues: firstly, the level of funding efforts required for basic research; secondly, the distribution of expenditure over infrastructures, single-lab research and collaborative research grants, both on a national and an international level; and thirdly, mechanisms to link up, where appropriate, national funding programmes between Member States.  

The fragmented nature of funding policies and the dispersal of resources create serious problems for the changing character and needs of basic research in the life sciences. A broad platform for discussion amongst all stakeholders involved in funding basic research in the life sciences in Europe is needed.

To contribute to this discussion the Commission will hold a conference on 13 December 2004[1]with aim of bringing together stakeholders from national and international funding organisations to explore new ways to co-operate in funding basic research in Europe. A number of high-level presenters will share their experiences with different approaches to funding of basic research in life sciences in Europe from both national and trans-national perspectives. The life sciences sector has been chosen as the focus for the conference because of the huge potential of the field for contributing significantly to the Lisbon objective for Europe to become the most competitive knowledge based economy.

Turning to the present, the Commission has just published the third call of FP6[2] which provides many opportunities for collaborative research in fundamental genomics. In the area Fundamental knowledge and basic tools for functional genomics in all organisms, which is the focus of this newsletter, a budget of  around  € 120 million  is available.  Topics open for proposals include  eleven tightly focussed topics open for proposals for integrated projects (IP) and networks of excellence (NoE). In contrast, for specific targeted research projects (STREP), proposals are invited for a range of more broadly defined scientific areas.  Where appropriate, the involvement of “small and medium-sized enterprises” (SMEs)  is highly encouraged in all topics in this fundamental genomics area.  

Proposals are particularly welcomed for two other types of projects, co-ordination actions (CA) and specific support actions (SSA).  These provide valuable opportunities for developing new strategies for European collaborative basic research. For example, one CA topic invites proposals to develop a strategy for the maintenance and sustainability of essential European database resources for all model organisms. A second example is an  SSA topic that asks for proposals to identify fundamental genomics areas of mutual benefit to Europe and certain “third country” regions (e.g. within Latin America; Indian peninsula; South-East Asia).  

Many other topics for genomics-related research can also be found in the other areas of Thematic Priority 1 Life sciences, genomics & biotechnology for health as well as Thematic Priority 5 Food quality and safety   and thematic Priority 6 Sustainable development, global change and ecosystems.

This edition of Genomics EU News includes news of some of the research projects selected in earlier calls. Work in different fields related to genomics, like molecular imaging techniques, zebrafish models, or membrane proteins is also highlighted. Longer-running projects are now beginning to generate important scientific results. So we are particularly grateful to Professor Sussman for sending us his views on his participation in one of our pilot Integrated Projects, SPINE.

Please get in touch with us if you want to send your opinions on this newsletter, results, suggestions or short articles related to FP6 or to fundamental genomics research in Europe. All contributions will be most welcome.

Bernard Mulligan is acting head of the unit Fundamental Genomics at the European Commission since 1 May 2004.

[2] Deadline for proposals: 16 November 2004. The workprogramme is available on CORDIS.

Second call brings wave of top-quality projects

After rigorous evaluation, 33 new projects in the field of fundamental genomics have been shortlisted for funding following the second call for proposals (deadline 13 November 2003) under the FP6 priority area ‘Life Sciences, Genomics and Biotechnology for Health’.

The very high quality of submitted projects has certainly not diminished since the first call, prompting the Commission to fund projects up to a budget of €168 million for this call.

The 32 projects were selected from 117 proposals. The final shortlist comprises nine Integrated Projects (IPs), three Networks of Excellence, 18 Specific Targeted Research Projects (STREPs), two Coordination Actions, and two Specific Support Action.

The NoEs and IPs cover the five key areas in fundamental genomics:

• Gene expression and proteomics
  The project shortlisted in this area will develop a transcriptome expression atlas of thousands of genes involved in mouse development, some of which have homologues implicated in human disease.

• Structural genomics
  One Integrated Project will explore structural data from RNA viruses to identify new antiviral drug targets. It will build up a strong European network able to respond rapidly to the threat of newly emergent viral threats such as SARS. A second project aims to improve current high-throughput crystallography and 3-D imaging methods to characterise yeast protein complexes, homologues of which are also found in humans.

• Comparative genomics and population genetics
  Developing a post-genomics ‘toolbox’ to facilitate phenotyping in complex diseases is the aim of the Integrated Project shortlisted in this area. Research teams working on methods for analysing molecular components, such as DNA, RNA, proteins and peptides, as well as on bioinformatics and statistics, will collaborate to speed up the potential of genomic epidemiology.

• Bioinformatics
  A shortlisted Network of Excellence, bringing together the top bioinformatics groups in Europe, responds to the need to better integrate bioinformatics tools into a common user interface. The project will use grid technology and other existing tools to ensure that the European biology community can access different sources of knowledge and information more efficiently.

• Multidisciplinary functional genomics approaches to basic biological processes
  Of the five Integrated Projects on the shortlist here, one aims to identify the genes underlying sensorineural hearing impairment and will explore their potential as therapeutic targets; another is looking at the molecular mechanisms involved in DNA damage and repair, using a variety of model organisms; the goal of a third project is to identify new genes involved in kidney development and disease; a fourth will explore the biological function of peroxisomes – cellular organelles important for the detoxification of cells by degrading hydrogen peroxide - and their role in human disease; and the fifth will investigate the fundamental molecular mechanisms of the retina development with the long-term aim to develop therapies for retinal degenerations. In addition, two Networks of Excellence have been shortlisted: one brings together European experts in immunology to study mouse mutants which model human immunological disease, and the other will identify new genes and pathways important in muscle disease and repair in a variety of model organisms.

The 18 smaller, more traditional projects (STREPS) shortlisted in this funding round will explore the following themes:

• Low abundance mRNAs and proteins
• Biological role of small RNAs
• Identifying and characterising multi-protein complexes of biotechnological interest
• Programmed cell death across the eukaryotic kingdom
• Comparative genomics in protozoa in relation to human health
• Development of new tools and approaches, including standardisation of protocols, to facilitate generation of new knowledge in functional and structural genomics
• In silico prediction of the structure of biological macromolecules. 

Besides these research projects, two Coordination Actions (CA) will help to integrate European research in functional and comparative genomics. They aim to co-ordinate respectively the resources and the tools available for the study of two animal models: mouse and Xenopus. In addition, by means of the two Specific Support Actions (SSA) selected, a Technology Platform for plant genomics and an ambitious training programme on membrane proteins will be established."

>> Second call

The Weizmann View of Being Part of SPINE

Joel L. Sussman

Being a partner in one of the first large-scale EC Scientific Integrated Projects -SPINE : Structural Proteomics in Europe (see http://www.spineurope.org) has had a most significant impact on biotechnological research at the Weizmann Institute of Science (WIS), in particular, and in Israel in general. Furthermore, through the close contact thus established with our European colleagues, some of our ideas have had an impact on the direction of structural proteomics in Europe.

The call issued by the EC, in November 2000, for ‘Expression of Interest’ in a large-scale European Structural Genomics/Proteomics initiative within FPV, aroused considerable interest within the European structural biology community. One of the issues discussed was whether such an effort could have a significant impact in the context of the large-scale NIH-funded US initiatives, which were already under way. A consensus began to form, which we at the WIS strongly supported, that SPINE should not do just ‘more of the same’, i.e. determine hundreds of 3D structures of ‘low-hanging fruit’ as a proof of principal, but rather, try to take advantage of some of the US technological advances to attack difficult problems in human health and disease.        

Once SPINE had been funded, the seed money that the WIS thus received was instrumental in transforming our structural proteomics initiative from an idea into reality. Largely due to the participation of the WIS in SPINE, the Israel Ministry of Science and Technology selected the WIS as the site for establishment of an ‘Israel Structural Proteomics Center (ISPC)’ (see http://www.weizmann.ac.il/ISPC), and provided substantial funding. Additional funding came from the Divadol Foundation, which has an interest in increasing the efficiency of scientific research in Israel. These three sources of funding facilitated the purchase of high-throughput robotic instruments for the ISPC and permitted the hiring of an outstanding scientific team.

The proposed model for anchoring of PON1 to the surface of HDL. Hydrophobic residues proposed to be involved in HDL-anchoring are shown with their side-chains in yellow. The grey line models the putative interface between HDL's hydrophobic interior and the exterior aqueous phase.

The ISPC node of SPINE has stimulated the interest in structural biology of biochemists and biologists within the WIS. They now realise that it is possible to determine 3D structures of proteins much more rapidly than they had thought, with 10 structures having been solved in the past 8 months (see http://www.weizmann.ac.il/ISPC/status.html). Two key 3D structures that were determined with the help of the ISPC are:

• Glucocerebrosidase: Mutations occurring in this enzyme cause Gaucher disease, a genetic illness that mainly affects Ashkenazi Jews. The solution of the structure of this enzyme may result in new therapies for this disease.

• Paraoxonase:a multi-purpose enzyme that has been shown to perform a variety of jobs in the body, including ridding the arteries of plaque-forming clumps of LDL (“bad” cholesterol) that lead to arteriosclerosis, and degrading toxic chemicals such as pesticides and nerve gases (for a recent popular report see http://news.bbc.co.uk/2/hi/science/nature/3671827.stm).

Furthermore, the SPINE node at the WIS has already had an impact on the Israeli biotech industry. Two SMEs are currently working with the ISPC in the development of new drugs.

We, at the WIS, have benefited enormously from being part of SPINE, since a substantial number of our scientists and students have been able to participate in workshops and work at other SPINE labs. Being part of SPINE allowed us to make contact with people at the bench, to have informal discussions by email and phone about technical problems, and to share experiences and protocols. Some of the ideas developed at the WIS, in particular in the area of bioinformatics, have been adopted by SPINE as a whole (see table). 

For the future, we would like to see an even more active SPINE web site for questions/answers regarding bottlenecks in various stages of structural proteomics, as well a depository of protocols in use in the different labs. It would also be invaluable for SPINE, and European structural biology as a whole, if we were to create a ‘bank’ of available plasmids used by the various SPINE partners to be distributed upon request.

Joel L. Sussman
Israel Structural Proteomics Center
Weizmann Institute of Science
Rehovot 76100 ISRAEL
Joel.Sussman@weizmann.ac.il

BIO2004 heralded a success

The European Commission’s DG Research was part of a large delegation attending the BIO2004 annual meeting held between 6 to 9 June in San Francisco, USA.

This proved to be a successful joint effort by DG Research's Life Sciences Directorates F (Priority 1) and E (Priority 5). It was the first time the European Commission had had a booth at the exhibition centre and had participated in the international BIO market place. Scientific officers from DG Research were on hand at the booth to answer questions about the Sixth Framework Programme (FP6) and other EC activities in the field of life sciences research. The EC's participation in BIO2004 focused on increasing awareness amongst European companies – and SMEs in particular – and third country organisations of the opportunities available to them in DG Research's FP6 and, secondly, to raise the visibility of European Commission activities in the life sciences community.

From left to right: Henriette van Eijl, John Claxton, Torbjoern Ingemannson, Irene Norstedt and Stephane Hogan.

TEMBLOR project on bioinformatics: Integr8 is operative

Integr8 has just been launched as a new browser that allows biologists to fully exploit the wealth of information available in completely sequenced genomes and their predicted proteomes at www.ebi.ac.uk/integr8. The site provides an easy way to quickly assess the molecular biology of a species: the nature of its genome, the protein families it contains (and those it does not contain), and the functional classification of its proteome (using the Gene Ontology). You can also view the latest publications on an organism, a list of all protein structures solved in that species, and comparisons with other species.

The first meeting of the RIBOREG project took place on 18-19 June 2004 in Sevilla.

RIBOREG is a STREP project funded under the first call in the area "Fundamental knowledge and basic tools for Functional Genomics in all organisms.
It includes 9 partners from 7 countries and 3 biotechnology companies (SMEs) sharing 27% of the 2,4 million euro budget.

This is the first project funded in FP6 on non protein-coding RNA research. The knowledge that will be generated by this project is urgently required to correctly exploit the huge amount of sequence data available. Considering that the actual protein-coding regions of genes comprise only 1.5% of the whole genomic information in humans, it is clear that more information is needed to understand the remaining 98.5%.
The aim of this proposal is to explore the role of non-coding genetic information by identifying novel non-coding RNA genes (ncRNAs) and analysing their mechanisms of action and impact on cell differentiation and disease. The partners will mine databases and use a large-scale genomic approach (RNomics) to search for new ncRNAs in diverse organisms (Arabidopsis thaliana, Caenorhabditis elegans, mouse) and for their human orthologues. They will construct ncRNAs gene-chips and study their expression in different genetic backgrounds and cellular or developmental conditions, including in cancer cell lines.
The main impact foreseen is the fostering of multidisciplinary transnational basic biological research in an emerging field that will give the opportunity for Europe to meet a major challenge. Among the other anticipated deliverables from the project is the strengthening of European industrial competitiveness.The SME partners will validate their existing technologies for the analysis of this unexplored region of the genome and will carry out demonstration activities that will bring direct benefits in terms of technological development.

Project coordinator:
Prof. Martin Crespi, Institute de Sciences du Vegetal, CNRS, crespi@isv.cnrs-gif.fr

The kick-off meeting of LYMPHANGIOGENOMICS took place on 24 May 2004 in Helsinki.

The Integrated Project LYMPHANGIOGENOMICS includes 13 partners, world class leaders in their field, from 7 European countries and 2 SMEs.

The lymphatic vasculature is essential for the maintenance of fluid balance in the body, for immune defence and for the uptake of dietary fat. Absent or damaged lymphatic vessels can lead to lymphedema, a chronic and disfiguring swelling of the extremities. In addition, lymphatic vessels promote metastatic spread of cancer cells to distant organs - a leading cause of death in patients with cancer, and a major obstacle in the design of effective therapies.
The aim of this project is to discover novel genes important for lymphatic vascular versus blood vascular development and function and to study the functional role and therapeutic potential of their gene products in lymphangiogenesis using state-of-the art technologies.

Legend Cutaneous lymphatic and blood vasculature. The lymphatics are stained with LYVE-1 antibodies (red), and the blood vessels with PECAM-1/CD-31 antibodies (green). The image is a 3D projection of a z-stack taken with a confocal microscope. [Image: Tuomas Tammela]

The consortium is going to use include large-scale knockout and knock-down of the mouse genome, embryonic stem (ES) technology, knock-down of zebra fish genes and positional cloning of genes involved in lymphangiogenesis and associated diseases. These studies will provide fundamental new understanding of the molecular and cellular basis of lymphangiogenesis and therefore enable scientists to develop therapies to suppress the growth of lymphatic vessels (eg. for cancer, inflammatory diseases) or to stimulate their growth (eg. for tissue ischemia, lymphedema).

Coordinator: Prof. Kari Alitalo, University of Helsinki, Finland, kari.alitalo@helsinki.fi

EU contribution: €9 million
Duration: 5 years

Structural Genomics: its impact on the aging world
1 September, 2004 , The Hague, Netherlands

In the frame of Genomics Momentum 2004, www.eu2004.nl, a minisymposium co-organized by the FP6 Network of Excellence '3D-EM' and the Integrated Project 'Interaction Proteome' is exploring the role of Structural Genomics techniques as tools to discover the genetic mechanisms of aging, and to the development of novel therapeutics in future biomedicine.
More information

Structural genomics and proteomics research: first joint meeting of European projects, Barcelona, 1-4 December 2004

Partners in FP6 structural genomics and proteomics projects are invited to take part in the first joint meeting in Barcelona later this year.

The event aims to create synergies between projects through networking opportunities, to give more visibility to the field, and to develop a proposal on future policies in structural genomics for FP7 and beyond.

Representatives from SPINE, scientific advisory boards, national funding agencies, industry and the press are also invited to attend.

For further details contact
Josefina Enfedaque
Scientific Officer - Structural Genomics
Directorate-General for Research
European Commission

Spotlight on 3DGenome

How does 2m of DNA fit into a cell nucleus only 0.01mm in diameter? The answer to this question is the subject of a new FP6 research project – 3DGenome – which will explore the function of the genome and its dynamic 3D structure within the cell.

Spatial distribution of DNA in the nucleus of a human cell. Here all DNA has the same colour (green). In the 3DGenome program different stretches of DNA will get a different colours. [Image: P.J. Verschure]

By changing the way in which DNA strands are folded up in a chemical complex called chromatin, individual cells can control which genes are switched on and off and ensure that they behave correctly at the right time and in the right place. A better understanding of this process should, for example, help to explain what goes wrong when cancer strikes.

The 3DGenome consortium members will develop state-of-the-art 3D light microscopy techniques, along with image processing and analysis tools to visualise DNA inside the cell. They will correlate the genome’s 3D structure with the expression of specific genes in human, mice and drosophila cells. Using this range of model systems will help establish which aspects of the 3D genome structure have been conserved through evolution and which are most likely to play an important role in gene regulation.

Project coordinator:

Roel van Driel
University of Amsterdam
The Netherlands
van.driel@science.uva.nl

Press release

EU contribution: €2.2million
Duration: 3 years

Cracking the membrane problem
E-MeP: European membrane protein consortium

The aim of the E-MeP Integrated Project is to tackle one of the major challenges in the biological sciences: membrane protein structure resolution.

Membrane proteins play an essential role in cellular processes by providing vital communication channels between the cell and its surroundings. They account for around 30% of encoded proteins and, as key drug targets, are of major interest to the pharmaceutical industry.

Membrane proteins are ubiquitous and have a pivotal role in cell life. Only a few structures have been determined, mostly prokaryotic. The picture shows the structure of the photosystem II from Thermosynechococcus elongatus [Science, 2004]. All oxygen we are breathing on this planet is generated from water by this enzyme using light energy from the sun. E-MeP will also target human membrane proteins of medical interest. [Image: So Iwata]

Structural problems

However, the properties of the cell membrane environment, with its water, lipid and protein components, impose certain structural and functional features on membrane proteins which make them much more difficult to study than the soluble proteins found elsewhere in the cell. Very few membrane protein structures have so far been resolved because of the difficulty in obtaining the large quantities of pure protein necessary for classic methods of 3-D structure determination. Indeed, many currently available drugs target membrane proteins whose structures are poorly understood. Gaining a better understanding of a target protein’s structure is a key step towards understanding its precise function and can help in the development of more specific and efficient drugs.

The E-MeP consortium aims to rise to the challenge of overcoming existing hurdles to the successful determination of membrane proteins. “Our strategy is to identify – and resolve – current bottlenecks at each step of the gene-to-protein-structure ‘pipeline’. Where possible, we will also develop new high-throughput technology platforms to speed up different steps in the process,” says Dr Roslyn Bill of Aston University, UK, E-MeP project coordinator.

Part of the project will include testing new prokaryotic and eukaryotic hosts in which to express the target proteins in sufficient quantities for subsequent purification and crystallisation. Structure determination of the whole protein will then take place using X-ray crystallography and other complementary methods, such as NMR and electron microscopy.

The kick-off meeting will take place on August 12-14 at the Imperial College of London.

Project coordinator:

Roslyn Bill
Aston University
UK
r.m.bill@aston.ac.uk
http://www.e-mep.org/

EU contribution: €10 million
Duration: 5 years

Hooking the potential of the zebrafish

ZF-models: zebrafish models for human development and disease

The ZF-models project consortium will exploit the enormous potential of the zebrafish as a model for human disease, to identify new drug targets and gain insight into pathways of gene regulation applicable to human development.

To genomics researchers the zebrafish is more than a popular aquarium fish. Although these striped fish bear little outward resemblance to humans, their genes and the way they function are very similar to those of humans. In addition, their small size, short generation time and the transparent embryos – which allow the observation of individual cell development – have made zebrafish a favourite model organism for biologists studying vertebrates using a functional genomics approach.

The zebrafish (Danio rerio) is a small tropical fresh-water fish which lives in rivers of northern India, northern Pakistan, Nepal, and Bhutan in South Asia. Due to its small size and ease of culture, the zebrafish has become a favourite model organism for biologists studying embryonic development.

Backwards and forwards

As part of the ZF-models project, the European zebrafish research community will undertake a large-scale chemical mutagenesis screening of 6 000 zebrafish genomes using recently developed genomics tools. This approach, known as ‘forward genetics’, allows researchers to trace the gene responsible for a specific phenotype generated by mutagenesis. The project will focus on genes of particular relevance to human disease, including those mutations that specifically affect adults. A ‘reverse genetics’ approach will also be used by knocking out specific genes thought to be implicated in certain phenotypic defects or key to certain biochemical pathways. These ‘knockout’ fish will be made available within and outside the consortium. In addition, transgenic fish capable of expressing green fluorescent protein (GFP) will be developed for the detection of morphological anomalies in the nervous system and to provide novel tools for gene expression analysis.

The short generation time, the large number of offspring and the transparency of the embryos make the zebrafish an ideal model organism to study the development of vertebrates using a genetic approach.

A European zebrafish database will integrate the large amounts of data generated by these different approaches. The consortium will also establish a European Working Group on Vertebrate Models to ensure a wider impact of the project beyond the zebrafish research community.

http://www.zf-models.org/

Project coordinator:
Robert Geisler
Max Planck Institute for Developmental Biology
Germany
robert.geisler@tuebingen.mpg.de

EU contribution: €12 million
Duration: 5 years

Seeing is believing
Molecular Imaging: integrated technologies for in vivo molecular imaging

The Molecular Imaging project aims to develop new non-invasive ways of imaging important biological processes in living systems, from the sub-cellular level to the whole animal, using a multidisciplinary approach.

Many of the current methods of imaging molecular interactions within the cell rely on in vitro or ex vivo techniques in which the cell tissue is isolated from its natural physiological environment. This severely limits the ability of researchers to gain a full understanding of the true dynamics of molecular processes in living systems and thus to understand the malfunctioning of these processes when disease strikes.

3D imaging of 700,000 CFSE loaded Cells implanted in a nude mouse resolved using Fluorescence Molecular Tomography in a non-contact geometry employing simultaneous surface extraction. What is shown is an axial section in the thorathic region with colorscale proportional to cell number. The head and anterior limbs of the animal are shown. [Image: J. Ripoll - V. Ntziachristos]

Probing techniques

The members of the consortium, which includes engineers, physicists, biochemists and biologists, will use their combined expertise to develop tomographic (cross-sectional scanning) and microscopic technologies with improved resolution, contrast and sensitivity, suitable for use in living systems and capable of visualising single molecules, such as proteins, at the nanometre scale. In addition, the project team is developing novel fluorescent probes in which specific structures or molecules in the cell are tagged with a fluorescent protein ‘lantern’ and then traced in real time using complementary microscopic and tomographic techniques. These probes can also be used to track gene expression and the results of transgenic manipulation by associating the gene of interest with a gene encoding for the fluorescent protein. Tracking the glowing signal from the fluorescent protein, linked to the target gene’s protein product, can give information on when and where the target gene is expressed in the body.

“By coordinating efforts from different disciplines, we will be able to develop powerful techniques with the potential to answer fundamental biological questions related to gene expression in living systems,” explains Jorge Ripoll, a consortium member based at the Foundation for Research and Technology in Greece.

Project coordinator:
Eleftherios Economou (economou@admin.forth.gr)
Foundation for Research and Technology
Greece
http://www.molimg.gr

EU contribution: €11 million
Duration: 5 years