EUR 23132
The sequencing of the human genome and many other genomes heralded a new age in human biology, offering
unprecedented opportunities to improve human health and to stimulate industrial and economic activity. The global
understanding of the complete function of approximately 22 000 human genes constitutes a major challenge
for understanding normal and pathological situations. To tackle this challenge, the European Commission made
fundamental genomics research a priority in the Sixth Framework Programme for RTD (FP6) (2002-2006).
The European Commission has allocated approximately `594 million in FP6 to fundamental genomics research
activities with the overall aim of fostering the basic understanding of genomic information by developing the
knowledge base, tools and resources needed to decipher the function of genes and gene products relevant to
human health, and to explore their interactions with each other and with their environment.
The present publication provides a brief description of the goals, expected results, achievements and expected
impact of all the projects supported during FP6 in the fundamental genomics priority area in the following scientific
sub-areas: the development of tools and technologies for functional genomics; regulation of gene expression;
structural genomics and proteomics; comparative genomics and model organisms; population genetics and
biobanks; bioinformatics; multidisciplinary fundamental genomics research for understanding basic biological
processes in health and disease; and the emerging area of systems biology.
During FP6, the European Commission has supported several systems biology initiatives which paved the way for
further developing the genomics and systems biology programme in the Seventh Framework Programme for RTD
(FP7) (2007-2013). The introduction provides an overview of the FP6 research policies and the steps taken to
strengthen the European Research Area in each of the scientific sub-areas, as well as the FP7 vision in genomics
and systems biology collaborative research.
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EUROPEAN COMMISSION
Directorate-General for Research
Directorate F- Health
Unit F.4- Genomics and Systems Biology
Christina Kyriakopoulou
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ISBN 978-92-79-08004-3
DOI 10.2777/49314
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European Commission
Directorate-General for Research
Directorate F- Health
Unit F4- Genomics and Systems Biology
Further information:
http://cordis.europa.eu/fp7/health/home_en.html
http://cordis.europa.eu/lifescihealth/genomics/home.htm
5
TABLE OF CONTENTS
Foreword 14
Abbreviations 15
Part A 16 Overview of FP6 and FP7 research policies in Fundamental Genomics and Systems Biology
Section 1 16 The importance of Fundamental Genomics research in the European Union’s Framework
Programmes for RTD
Section 2 19 Fundamental Genomics programme in FP6: sub-areas and their objectives
Section 3 20 Scientific Excellence and impact of European Fundamental Genomics Collaborative Research
Section 4 22 The way forward in FP7: From Fundamental Genomics to Systems Biology
Section 5 25 Content of the present publication
Section 6 27 EC’s financial contribution in Fundamental Genomics & Systems Biology
Collaborative Research
Section 7 27 Scientific sub-areas supported in the FP6 and FP7 in Fundamental Genomics and
Systems Biology
Annexes 64 Basic facts and figures for Fundamental Genomics activity area
Annex I 64 Funding instruments-schemes in FP6 and FP7
Annex II 69 Development of the specific scientific topics for calls for proposals
in the FP6 Fundamental Genomics programme
Annex III 70 European Commission’s strategic workshops in different scientific areas
of fundamental genomics and systems biology
Annex IV 72 Evaluation process in the FP6 and FP7 Fundamental Genomics programme
Annex V 75 Evaluation criteria in FP6 and FP7
Annex VI 78 Basic facts and figures for Fundamental Genomics activity area in FP6
4.2 Rat
4.3 Zebrafish
6. Bioinformatics
7.5 Chronobiology
Part C Indexes
INSTITUTION AND
COORDINATOR INDEX 493
The European Commission identified the importance of genomics quite early, and has played
a cohesive role in addressing the fragmentation of the genomics and post-genomics research
community in Europe by funding collaborative research projects via the EU Framework Pro-
grammes for RTD. The rationale for structuring and integrating fundamental genomics research
at European level to tackle fragmentation and research capacity gaps is based on its immense
potential contribution to the understanding of the processes underlying human disease, and
hence offering unprecedented opportunities to improve human health and stimulate industrial
and economic activity. This research requires a collaborative approach, is by nature highly
multidisciplinary, and needs expertise and critical mass that do not exist in a single laboratory.
Integrated multidisciplinary research and a strong interaction between high-throughput tech-
nology development and biology are vital in the fundamental genomics field for translating
genome data into practical applications.
The European Commission has allocated some `594 million over four years in FP6 for fun-
damental genomics research activities with the overall aim to foster the basic understanding
of genomic information by developing the knowledge base, tools and resources needed to
decipher the function of genes and gene products relevant to human health, and to explore
their interactions with each other and with their environment. The present publication provides
a brief description of the goals, expected results, achievements and expected impact of all
the projects supported during FP6 in the Fundamental Genomics priority area in the following
sub-areas: tools and technologies development for functional genomics; regulation of gene
expression; structural genomics and proteomics; comparative genomics and models organ-
isms; population genetics and biobanks; bioinformatics; and multidisciplinary fundamental
genomics research for understanding basic biological processes in health and disease and
the emerging area of systems biology. During FP6, the European Commission supported sev-
eral systems biology initiatives which paved the way for further developing the genomics
and systems biology programme in the Seventh Framework Programme for RTD (FP7) (2007-
2013). The introduction provides an overview on FP6 research policies and the steps taken to
strengthen the European Research Area in each of the scientific sub-areas, as well as the FP7
concept in genomics and systems biology collaborative research.
The European Commission via its Life Sciences and Health programme has been acting as
a catalyst for strengthening European excellence in genomics and systems biology research.
The path to scientific discovery and innovation is long and complex and we have realised
that further investment will continue to be necessary for this important area. We are proud of
the European scientists who collaborate in top-class research projects and we are certain that
these projects will lead to substantial advances in the understanding of the links between the
human genome and diseases, strengthen Europe’s position in this important field of research,
and eventually benefit society.
Manuel Hallen
Acting Director
Health Research
Section 1
The importance of fundamental genomics research in
the European Union’s framework programmes for RTD
Over the last 23 years, the European Union (EU), via the implementation of subsequent EU Framework Pro-
grammes (FPs) for supporting Research and Technological Development (RTD) activities in the European Union,
has funded European collaborative and multidisciplinary research projects. This multi-laboratory, multinational
collaboration represents the ‘reason of existence’ of the FPs for RTD, often essential for assembling critical mass,
tackling fragmentation and strengthening European excellence in important research areas. The expected impact
lies in enabling breakthroughs in important research areas in order to boost European biomedical and biotech
industry competitiveness, and ultimately to improve citizens’ quality of life.
A significant part of different FPs’ budgets is dedicated to supporting collaborative research in life sciences and
biomedical research. The overall budget of the Sixth Framework Programme for RTD (FP6) was `17.5 billion, of
which an important proportion of `2.5 billion was allocated to the thematic priority of ‘Life Sciences, Genom-
ics and Biotechnology for Health’ in the period 2002 - 2006. The overall budget of the Seventh Framework
Programme for RTD (FP7) is `50.5 billion; it will run for seven years, with approximately `6 billion dedicated
to health-related collaborative research support.
` billion
60
50
40
30
20
10
The European Research Area (ERA) was launched in 2000 by the EU as a key concept in implementing the Lisbon
strategy to make the EU “the most dynamic and competitive knowledge-based economy” by 2010; this was later
followed by the goal to increase spending on R&D in the EU up to 3% of the gross domestic product (GDP), where
two thirds would originate from private investments. FP6 set the implementation of the ERA as its major objective
and addressed the fragmentation of EU research more intensively.
■ a European ‘internal market’ for research, where researchers, technology and knowledge can circulate freely;
■ effective European-level coordination of national and regional research activities, programmes and policies;
The FP is the main financial instrument to implement the ERA at EU level, but it is clear that many other EU initia-
tives and particularly initiatives at national and regional level will have to be undertaken.
Fragmentation
Under-resourcing
National
programmes
Open European
Coordination research policy
Framework
programme
European
organisations
The European Commission (EC) identified the importance of genomics quite early, and has played a cohesive
role in addressing the fragmentation of the genomics and post-genomics research community in Europe by fund-
ing collaborative research projects via the EU FPs for RTD. The rationale for structuring and integrating funda-
mental genomics research at European level to tackle fragmentation and research capacity gaps is based on
its immense potential contribution to the understanding of the processes underlying human disease, and hence
offering unprecedented opportunities to improve human health and stimulate industrial and economic activity.
This research is by nature highly multidisciplinary, requires a collaborative approach, and needs expertise and
critical mass not available in any single laboratory. Integrated multidisciplinary research and strong interaction
between high-throughput (HTP) technology development and biology is vital in the fundamental genomics field
for translating genome data into practical applications.
0OOLINGĺANDĺLEVERAGINGĺRESOURCES
Resources are pooled to achieve critical mass
Leverage effect on private investments
Interoperability and complementarity of big science
&OSTERINGĺHUMANĺCAPACITYĺANDĺEXCELLENCEĺINĺ34
Stimulate training and international mobility of researchers
Improve S&T capabilities
Stimulate competition in research
"ETTERĺINTEGRATIONĺOFĺ%UROPEANĺ2$
Create scientific base for pan-European policy challenges
Encourage coordination of national policies
Effective comparative research at EU-level
Efficient dissemination of research results
Between 1990 and 2002 (from the Third Framework Programme (FP3) through the Fifth Framework Programme
(FP5)), the EU invested in genomics research. This resulted in several major breakthroughs: the sequencing of the
first eukaryotic genome (yeast), the sequencing of the first plant genome (Arabidopsis thaliana), and the assem-
bling of the physical and genetic maps of the human genomes — important and necessary tools for the further
sequencing of the human genome.
During FP5 (1998–2002), the EC invested `120 million in genome research. In 2002, `39.4 million was pro-
vided to three large-scale research projects in genomics research for human health: GenomEUtwin, a major effort
in population genetics (see www.genomeutwin.org); EUMORPHIA, a large integrated project (IP) devoted to the
development and standardisation of mouse models phenotyping tools (see www.eumorphia.org); and SPINE, a
major structural proteomics effort that solved approximately 300 new protein structures (www.spineurope.org).
These three projects, the first of such scale in FP5 in the life sciences, played an important role in structuring the
research community in the respective areas.
The publication of the first complete sequence of the human genome in 2001, as well as the sequencing of many
other genomes, heralded a new age in modern biology and biomedicine, offering unprecedented opportunities
to improve human health and to stimulate industrial and economic activity. If science was looking for a milestone
to mark the entry into the 21st century, it seems that revealing the sequence of the letters of the ‘book of life’ was
the most important one. Researchers in the post-genomics era have doubled their efforts, with the major goal of
‘reading’ the ‘book of life’, and understanding its ‘syntax’ and ‘language’ by putting the ‘words’ (our genes and
their functions) in the correct order.
The three billion ‘letters’ that make up our genetic code contain all the information needed to turn a fertilised egg
into an adult human being. Thanks to the human genome project, we now know the sequence of letters constitut-
ing the approximately 22 000 human genes.
However, the global understanding of the complete function of our genome, including the function of approxi-
mately 22 000 human genes and the interactions amongst them and with the environment, still constitutes a
major challenge for the understanding of normal and pathological situations.
DNA and protein microarrays and other technologies for HTP molecular profiling have expanded our horizons
and have provided a context for the information on the human organism: there are approximately 20 000 to
25 000 protein-encoding genes, more than 100 000 transcript splice variants of those genes and perhaps 106
protein states of possible functional significance.
All the latest technological and knowledge breakthroughs and the accumulation of HTP novel data continue
to highlight how little we still know about the effect of genes on the development of healthy and diseased
phenotypes.
Therefore, to tackle these challenges, the EC made genomics and post-genomics research a research priority in
FP6 (2002–2006). Indeed, of the total `2 500 million allocated to the priority of ‘Life Sciences, Genomics and
Biotechnology for Health’, approximately `594 million was invested over four years in the FP6 Fundamental
Genomics programme. Investing substantially in this EU Fundamental Genomics programme area was also im-
portant in meeting the scientific community’s strong expectations, illustrated by the high number of expressions
of interest (550) submitted in this area during the 2002 launching of FP6.
Section 2
The Fundamental Genomics Programme in FP6:
sub-areas and their objectives
Functional genomics is the branch of genomics that determines the biological function of the genes and their
products using the development and application of global (genome-wide or systems-wide) experimental ap-
proaches (i.e. genomics, transcriptomics, proteomics, in silico functional prediction, etc.).
Fundamental genomics
Fig. 4: Fundamental genomics research in the life sciences and biomedicine landscape
The EU FP6 Fundamental Genomics Programme identified its strategic objectives: to foster the basic understand-
ing of genomic information by developing the knowledge base, tools and resources needed to decipher the
function of genes and gene products relevant to human health, and to explore their interactions with each other
and with their environment.
■ Gene expression and proteomics with the aim of enabling researchers to better decipher the functions
of genes and gene products, as well as to define the complex regulatory networks (biocomplexity) that
control fundamental biological processes. Research focused on developing high throughput tools and
approaches for monitoring gene expression and protein profiles and for determining protein functions
and protein interactions.
■ Structural genomics with the overall objective to enable researchers to determine, more effectively and at
a higher rate than currently feasible, the three-dimensional (3-D) structure of proteins and other macromolecules,
important for elucidating protein function and essential for drug design. Research focused on developing HTP
approaches for determining high-resolution 3-D structures of macromolecules.
■ Comparative genomics and population genetics with the goal of enabling researchers to use well-
characterised model organisms for predicting and testing gene function and to take full advantage of specific
population cohorts available in Europe, so as to determine the relationship between gene function and health
or disease. Research focused on developing model organisms and transgenic tools, and developing genetic
epidemiology tools and standardised genotyping protocols.
■ Bioinformatics with the aim of enabling researchers to access efficient tools for managing and interpreting
the ever-increasing quantities of genome data, and for making it available to the research community in
an accessible and usable form. Research focused on developing bioinformatics tools and resources for
data storage, mining and processing, and on developing computational biology approaches for in silico
prediction of gene function and for simulation of complex regulatory networks.
With the rise of the era of systems biology, which signalled a new approach in understanding biological processes,
the latter sub-area supported pilot projects applying systems biology approaches for understanding basic biological
processes in health and disease.
Although these areas represent different sections of the fundamental genomics programme during FP6, many
projects were found to be cross-cutting in nature, using multidisciplinary approaches. For this reason, the authors
decided to present the projects funded in fundamental genomics according to common scientific theme, rather than
to use the ‘artificial’ sections mentioned above: this is more comprehensible for the reader. The grouping of all the
projects funded in FP6 in scientific sub-areas is presented in Section 7, along with an introduction explaining which
EC Actions reinforce which areas, the steps taken towards the ERA and a set of representative project examples.
Section 3
Scientific excellence and impact of European
fundamental genomics collaborative research
The EC identified the importance of genomics quite early, and has played a cohesive role in addressing the frag-
mentation of the genomics and post-genomics research community in Europe by funding collaborative research
projects via the EU FPs for RTD. The rationale for structuring and integrating fundamental genomics research at the
European level to tackle fragmentation and research capacity gaps is based on its immense potential contribution
While it is still premature to predict the success of European projects supported under the Fundamental Genomics
programme under FP6, one may conclude that EU is funding top-class, ambitious and state-of-the-art projects, involv-
ing excellence in Europe (as exemplified by the seven European Nobel prize winners participating in projects in
fundamental genomics):
■ Christiane Nüsslein-Volhard: Nobel Prize Winner in Physiology or Medicine 1995 (project ZF-MODELS)
■ Rolf Zinkernagel: Nobel Prize Winner in Physiology or Medicine 1996 (project MUGEN)
■ Tim Hunt: Nobel Prize Winner in Physiology or Medicine 2001 (project MITOCHECK)
The first FP6-funded projects started in 2004, some have already been finalised, others are still ongoing. It is al-
ready evident that many of these projects have already generated major discoveries on novel gene functions, and
resulted in high-level publications (see project websites for further details). Most importantly, these projects have
played an important role in integrating the research community in Europe, thereby increasing their visibility at na-
tional, European and international level. They have also substantially contributed towards reducing fragmentation
of research in Europe in their respective fields, thereby implementing the concept of the ERA and creating a real
multidisciplinary integrated programme of activities, as is illustrated with relevant figures in each sub-area’s activi-
ties description (see Section 7).
All the projects funded in the area of fundamental genomics have very ambitious objectives. To achieve these
objectives, it is necessary to apply a multidisciplinary transnational approach and to create the necessary critical
mass of researchers utilising a large set of different cutting-edge technologies. This multidisciplinary approach
is only possible at European level by networking the research capacities and excellence available in different
countries via the EU collaborative projects (CPs).
KI
KI LAU
CSIC
LAU
CNRS CNRS LU
EBI
LU
BIOZ
MPI-B
FEI
MPI-F
UOXF
UOXF
EBI Birkbeck
FEI
UU
Imperial
Birkbeck Imperial
UU
Fig. 5: The structuring effect and the added value of collaborative projects: an example
of active interactions between partners at the start point to the mid-term of a four year project
The last decade has witnessed unprecedented advances in the life sciences. The rise of genomics after the se-
quencing of the human and other genomes has revolutionised biology, with genome sequences becoming the
‘periodic table’ of biology. The spectacular development of the field of functional genomics and other ‘-omics’
research has dramatically changed the research landscape in the life sciences.
Life sciences research is moving away from a reductionist approach towards a new paradigm shift and a systems
biology approach that attempts to understand biology in an integrative manner as large amounts of novel data
become available.
In this new era of biology, scientists combine data, produced by a multidisciplinary set of functional genomics
tools and technologies, into biological models with the power of computer science, mathematics or engineering
to understand the phenomena of life. Researchers are increasingly realising that complex organisms cannot eas-
ily be subdivided into individual, independent components. Rather, genes, proteins, cells and organs interact
with each other and the environment in numerous, complex ways.
Systems biology aims to shed new light on these interactions, which are vital for the holistic understanding of
many major diseases such as cancer and diabetes.
The FP7 programme (2007–2013) has already been launched and is expected to play an important role in devel-
oping the field of systems biology in Europe by supporting the necessary critical mass of multidisciplinary expertise
(‘-omics’, mathematics, physics, etc.) needed to produce the complex models underlying important biological proc-
esses. This will require modelling of complex systems involving networks of tens of thousands of genes, gene prod-
ucts and other molecules. By understanding these biological processes in their complexity, systems biology promises
to make real progress towards understanding, preventing and combatting major complex diseases.
Although the deciphering of the human genome sequence represents a major step towards understanding human
biology, many questions still remain unanswered, including the function of most of the genes. New large-scale
data-gathering initiatives (e.g. population genetics including biobanks, large-scale proteomics, etc.) will be es-
sential for generating new knowledge on gene functions and their interactions in complex regulatory networks in
health and disease for future systems biology approaches.
Furthermore, to catalyse progress in functional genomics and systems biology, it is important to develop new and
improve existing ‘-omics’ high-throughput (HTP) research tools. The tools will catalyse experimental progress by
enhancing the generation and acquisition of data by orders of magnitude, and by significantly increasing our
knowledge base to gain insight into the functioning of cells, tissues, organs and entire organisms.
Based on the continuation concept and building on the strong FP6 European collaborative activities that have tak-
en place, the priority area of fundamental genomics is evolving towards the systems biology era. The structure of
the Genomics and Systems Biology programme in FP7 (2007–2013) ) is subdivided in the following sub-areas:
■ High-throughput research
The objective of this activity is to develop new research tools for modern biology that will significantly enhance
data generation and improve data and specimen (biobanks) standardisation, acquisition and analysis. The focus
will be on new technologies for:
■ gene expression
■ structural genomics
■ bioinformatics
■ systems biology
Functional genomics is a field of research offering many opportunities for technological innovation. New
tools and technologies will be essential to enhance our knowledge on gene functions in health and dis-
ease: increasing data output and considerably decreasing the cost for sample analysis will permit the
transfer of these technologies to the clinical environment. Developing new HTP research tools and technolo-
gies for collecting and processing vast amount of new and high-quality data will dramatically increase our
knowledge of complex biological processes.
The development of these new tools and technologies requires a large multidisciplinary and coordinated
effort, involving expertise in molecular biology, engineering, robotisation, electronics, material sciences and
physics. Only coordinated efforts at European level can harvest this diverse expertise with the common goal
of developing new cutting-edge technologies. Importantly, any technological innovation obtained through a
coordinated European effort greatly facilitates wider access to these new technologies in Europe.
In several technological areas (e.g. imaging, proteomics, structural genomics, transgenics), Europe is very
competitive and a wide range of direct medical applications have been or are being developed. The
integrated collaborative efforts launched in FP6 and future efforts in FP7 will reinforce this competitive posi-
tion. The development of groundbreaking technologies will support knowledge-based European competi-
tiveness and their applications are expected to have a great impact on biomedical and biotechnological
industry, including small to medium-sized enterprises (SMEs).
The objective is to use HTP technologies to generate data for elucidating the function of genes and gene products
and their interactions in complex networks. The focus will be on the following:
■ genomics
■ proteomics
■ population genetics
■ comparative genomics
■ functional genomics
New large-scale and systematic data-gathering initiatives in functional genomics (e.g. on the human pro-
teome) will be essential for human biology in providing new knowledge on gene functions. Furthermore,
standardisation of approaches will be achieved by developing European norms to facilitate efficient data
interchange. The data will be freely available for the scientific community in Europe.
In the recent past, several large-scale European initiatives were proven to be successful. In FP6, several
new initiatives have been initiated, including, for example, the large-scale genome annotation programme,
the whole mouse genomes in situ hybridisation projects and several structural genomics efforts.
Many Member States have cutting-edge post-genomics infrastructures, capacities and expertise. However,
to launch new large-scale data-gathering initiatives, these will need to be networked in a well-coordinated
and integrated effort that will generate the necessary critical mass of scale and scope. They will offer pos-
sibilities to smaller Member States with more limited resources and capacities. Furthermore, considerable
economy of scale and resources can be achieved by networking these research capacities in a coordi-
nated and integrated way. This coordinated approach at European level has proven to be successful for
several large data-gathering initiatives: the sequencing of the first yeast and plant genomes, and more
recently, the determination of the 3-D structure of proteins important for human health, via the structural
genomics collaborative efforts.
These large-scale initiatives require a multidisciplinary approach involving different types of expertise.
One of the bottlenecks in the translational process is how to translate a massive amount of data into useful
knowledge that is directly applicable. For this purpose, it is important to closely associate the bioinfor-
matics communities with these initiatives, so as to develop the integrated databases necessary for wide
dissemination of results. Industry must be closely associated with these efforts, providing the required
technical innovation and assistance.
■ Systems biology
The focus will be on multidisciplinary research that will integrate a wide variety of biological data and will de-
velop and apply system approaches to understand and model biological processes.
Solving biological problems in health and disease requires understanding of complex networks, involving
tens of thousands of genes, gene products and other molecules. To further our understanding of biologi-
cal phenomena, there is a need for quantitative approaches and systematic modelling, and analysis of
the enormous amounts of information gathered by HTP technologies. With such approaches, collectively
termed ‘systems biology’, we can gain new insight into the functioning of living systems, from the mo-
lecular levels to the organism and population levels. This research involves a wide variety of disciplines,
including modelling and simulation of the complex dynamic interactions. Eventually, systems biological
research will open the way towards predictive biology and medical applications, when sufficiently power-
ful models, fed with enormous amounts of data from different sources, become widely available.
Projects operating in this category will contribute to the ERA by combining dispersed forces from around Eu-
rope. Scientists working on a particular system system (e.g. a cell, an organ or a disease) in different locations
will be able to work together towards a thorough understanding of the systems. Enabling this type of research
to be carried out at European level will secure Europe’s place in an increasingly competitive field and so help
employment prospects, industrial development (including SMEs) and wealth creation. Exploiting biological
data in an integrated way is one of the most cost-effective means of supporting all life sciences, as well as
helping to achieve the Lisbon objectives with the move towards a dynamic knowledge-based society.
Such an interdisciplinary approach is difficult, if not impossible, to carry out in a single institute, company
or even a single country. This research can only be undertaken in a large consortium which ideally should
be multinational. The requirement for such varied expertise renders the area ideal for European pro-
Under FP6, several projects are under way, that either work towards enabling system biology, or gather
data that are suitable for such approaches (examples are Biosapiens and Eurohear). Many researchers
currently working on various systems are moving into systems approaches and the trend is likely to con-
tinue in the coming decade. The genome era has enabled us to accumulate enormous quantities of data
on both our genome and that of other organisms. The amount of data is certain to increase exponentially
for the foreseeable future. Paradoxically, utilising this data is becoming feasible on the one hand, and
increasingly complex on the other. The high hopes for new drugs and other treatments from the genomic
data can only become reality if the potential is realised through approaches such as systems biology.
Multidisciplinary projects :
s "IOLOGY
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s -ATHEMATICS MODELLING
s #OMPUTATIONALDATABASE TOOLS
s #LINICAL RESEARCHHUMAN GENETICS
Section 5
Content of the present publication
Although the sub-areas set out in Section 2 represent different sections of the fundamental genomics programme
in FP6, many projects were found to be cross-cutting in nature, involving multidisciplinary approaches. For
this reason, we thought the reader would find it clearer to present the list of projects funded in fundamental
genomics arranged according to common scientific theme rather ‘artificially’ distributed based on the action
lines mentioned above.
The present publication provides a brief description of the goals, expected results, achievements and expected
impact of all the projects supported during FP6 in the fundamental genomics priority area in the following scien-
tific sub-areas:
■ bioinformatics
For each of these sub-areas, an introductory section describes the importance and impact in the post-genomics
era of each field, including highlights from several projects and a short description of the activities implemented
in the FP7 first call for proposals. The introductory section also provides an overview of FP6 research policies and
the steps taken to strengthen the ERA in each of the scientific sub-areas, as well as the FP7 vision in genomics and
systems biology collaborative research. However, owing to space limitations in this publication, we could not
highlight all 130 projects funded in the fundamental genomics programme, in the introductory section. Naturally,
this by no means minimises the importance of the projects not cited.
Number of EC financial
Scientific sub-area projects contribution
(million `)
Tools and Technologies
20 68.0
for Functional Genomics
Regulation of Gene Expression 6 32.6
Structural Genomics
19 87.2
and Structural Proteomics
Comparative Genomics
15 82.4
and Model Organisms
Population Genetics and Biobanks 10 19.4
Bioinformatics 5 32.0
Multidisciplinary Approaches
32 219.4
for Basic Biological Processes
Section 6
EC financial contribution in fundamental genomics
and systems biology collaborative research
The EU FP6 thematic activity on ‘Life Sciences, Genomics and Biotechnology for Health’ has had a clear focus
in the post-genomics era, rising to the challenges following the sequencing of the human and other organisms’
genomes. More specifically, the Fundamental Genomics Research programme received support of approximately
`594 million under FP6 for a large number of collaborative projects (CPs) (small- to medium-scale (89) and large-
scale (41)), out of a total `2 500 million allocated to the priority of ‘Life Sciences, Genomics and Biotechnology
for Health’. The EC has committed approximately `635 million for 87 projects under Health research for the FP7
first call selected projects which started in the beginning of 2008. More specifically, in the Genomics and Systems
Biology area, 14 large-scale integrating projects were supported, constituting `161.5 million (for further details,
see Table 1). Specific explanatory notes on the definition of the funding instruments in FP6, namely Integrated
Projects (IPs), Networks of Excellence (NoE), Specific Targeted Research Projects (STREPs), Co-ordination Actions
(CAs) and Specific Support Actions (SSAs) are presented in Annex I of this publication.
Section 7
Scientific sub-areas supported in FP6 and FP7
in fundamental genomics and systems biology
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺFUNCTIONALĺGENOMICSĺ
All processes in biology and medicine reflect the flow of information from the genome of the organism to its
phenotype. Since the identification of the structure of the DNA molecule more than 50 years ago, progress in
understanding these processes has been driven by new technologies such as cloning, DNA sequencing, meas-
urements of ribonucleic acid (RNA) and protein, and use of robotics and microarrays. The genome sequencing
project has created a milestone for the deeper understanding of the function of the genes in a genome-wide, HTP
manner and set the challenges for the post-genomic era in the area known as functional genomics.
Functional genomics focuses on a series of dynamic aspects of cellular biology such as gene transcription,
translation and protein-protein interactions, including function-related aspects of the genome itself, such as muta-
tion analysis and the measurement of molecular activities. It utilises the development and application of global
(genome-wide or systems-wide) experimental approaches e.g. genomics, transcriptomics, proteomics, in silico
(in italics) functional prediction, etc.). HTP technologies are a hallmark of functional genomics experimentation,
with their capacity for collecting data on a genome-wide scale.
Despite all the progress being made, there are a number of bottlenecks currently affecting functional genomics
research. The success of functional genomics lies in the development of novel tools to solve the practical limitations
it suffers today. It should also be noted that there is a high degree of fragmentation of technologies, resources and
expertise, which makes it difficult to exchange information and address the bottlenecks in a coordinated effort.
Such collaboration is particularly important in view of the speed with which these technologies are moving and
also because of their multidisciplinary nature. Another important issue is the tools standardisation aspect: this is
required to provide high-quality reproducible data and to enable valid exchange and comparison of experimental
data. In addition, due to the large quantity of data produced by these techniques, the development of sophisticated
bioinformatics tools is necessary to increase the power of the functional genomics technologies. Most importantly,
the development of new tools and technologies in functional genomics requires a large multidisciplinary and coor-
dinated effort involving expertise in molecular biology, engineering, robotisation, electronics, material sciences and
physics. Only coordinated efforts at European level can bring together this diverse expertise with common goals of
developing new cutting-edge technologies, and therefore the area is well suited for EU support.
FP6 activities
In order for Europe to keep its competitive position in the development of new and improved functional genom-
ics tools, a substantial number of projects have been supported in FP6 and several important actions have been
launched in the first three FP7 calls for proposals.
In summary, the fundamental genomics programme in FP6 supported projects that aimed to improve existing or
develop new tools and technologies for functional genomics research.
The projects addressing such technologies are grouped in four categories, namely:
Plenty of other projects developing tools and technologies are presented in the different sub-areas of structural
genomics, model organisms, population genetics and bioinformatics in the following sections.
The FP6 European projects have been successful in bringing together the tools, the developers and the experi-
mentalists for developing the most appropriate state-of-the-art technology and for validating them in experi-
mental conditions. The HTP, high-precision technologies that are being established as a result of FP6-related
projects are expected to be of major importance to research, improving the competitiveness of Europe on the
world stage. Importantly, any technological innovation obtained through a coordinated European effort greatly
facilitates wider access to these new technologies in Europe and to the international scientific community. The
future applications of functional genomics technologies in health research are endless: cellular mechanisms
can be delineated, gene expression chips are already being used in early diagnosis, and proteins potentially
have enormous value as clinical biomarkers.
FP7 activities
The EC recognises the immense potential of the technologies in functional genomics for innovation and strength-
ening of European biotechnological and biomedical industry competitiveness. Therefore, FP7 has prioritised the
During the FP7 first call for proposals, EC supported three large integrating projects launched in 2008, amount-
ing to `36 million overall, in the following subjects:
■ tools and technologies development for spatial and temporal proteomics (PROSPECTS);
During the FP7 second call for proposals, a broad topic on SME-driven small-scale focused research CPs for
developing tools and technologies for HTP research was published. Several projects were selected for funding
amounting to approximately `30 million, covering areas on tools for gene expression, proteomics, sequencing,
phenotyping (currently under negotiation). The funding upper limit was `3 million EC contribution per project,
with 40% allocated to SMEs, which is expected to reinforce SMEs’ scientific and technological bases.
The EC, continuing its efforts in the functional genomics tools area, published the FP7 third call for
proposals in September 2008, with the aim of attracting proposals in the following areas:
■ HTP tools and technologies to analyse samples in large-scale human biobanks, which will
deliver high-quality and standardised data and accelerate epidemiological studies and biomarker discovery;
■ tools, technologies and resources for the characterisation of protein functions, which will
help to overcome bottlenecks in the investigation of protein functions in cells, leading to a better under-
standing of biological processes in health and disease.
For the first time in EU CPs in health research, a two-stage selection process will be implemented, with proposal
topics that are broader in scope and that will invite a larger number of pre-proposals (of maximum 5 to 10 pag-
es) for the first stage. In this way, the scientific community will be consulted for their ideas on research projects,
aiming to keep Europe at the forefront of technology and resources development in HTP research.
Europe is very competitive in the development of several groundbreaking technologies for functional genomics,
and their applications are expected to have a great impact in biomedicine and in the biotechnology industry,
including SMEs. Only coordinated efforts at European level can gather this different expertise with the common
goal of developing new cutting-edge technologies. Therefore, the FP7 Health priority via its Genomics and Sys-
tems Biology programme will continue its support for catalyzing progress in this important area.
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺGENEĺEXPRESSIONĺ ĺ
The ability to functionally explore the effect of genes on cellular phenotypes and signalling in a HTP fashion is of
fundamental importance in all fields of life sciences and biomedicine and has also attracted the attention of the
biotechnology and biomedical industries.
Developments in large-scale, high throughput technologies and robotics now allow researchers to simultaneously
profile vast numbers of different genes and gene products in parallel. Examples are DNA microarrays, where
many thousands of genes are spotted onto an area no bigger than a microscope slide, allowing researchers to
sample thousands of genes in parallel for expression analysis in health and disease.
Recent years have seen the rapid growth of techniques for HTP analyses of genes, transcripts, proteins and cells
using microarrays, but current methods still capture only a small fraction of the information embodied in the
biological molecules. Methods are needed to detect nucleic acids and proteins in single cells, and in complex
samples even at the level of single molecules, to overcome the limitations imposed by techniques currently being
applied in heterogeneous populations of cells. The success of novel technologies will lie in breaking through
the practical limitations it suffers today, in terms of sensitivity, accuracy, and ‘noise’ levels. A great challenge
still remains the intensive interplay between tools developers and experimentalists, and between academy and
industry: collaborative and coordinated efforts at the European level are required to tackle this. In addition, the
optimisation of standardised HTP technologies to study gene expression will remain a requirement for the future,
as well as the development of ultra-precision technologies and devices.
FP6 activities
In summary, the FP6 projects funded in this sub-area may be classified into two categories:
With already existing array technologies serving as a starting point, the IP MolTools is developing a new
set of HTP methods with the aim of increasing sensitivity and precision, and enabling analyses at the level
of single DNA, RNA or protein level at a considerable lower cost. EMERALD aims to coordinate a discus-
sion on reproducibility, variability and comparability of microarray experiments at different platforms and to
overcome the limitations of microarray technologies in terms of reproducibility and sensitivity. The resolution
of these issues will facilitate the translation of microarray technology in a clinical setting. TRANSCODE
develops open source tools using bioinformatics and large-scale experimental approaches for the prediction
and verification of the functional role of regulatory elements controlling gene expression, and for the identifi-
cation of transcription factors (TFs) binding sites. AUTOSCREEN’s goal is the establishment of an innovative,
automated instrument for HTP and high-content screening that will permit the qualitative and quantitative
monitoring of cellular constituents (RNA, proteins, and metabolites) in living cells.
2. Projects developing tools for gene expression, which are applied to the study
of disease mechanisms
REGULATORY GENOMICS aims to develop novel tools and methods for the determination of tran-
scription factor binding specificity, and to apply these techniques for determination of the binding spe-
cificities of TFs linked to cancer. This information will subsequently be used for computational identifica-
tion of ‘regulatory’ SNPs (rSNPs) that are predicted to affect transcription factor binding. The principle
objective of the project MODEST is the development and use of modular devices as well as protocols
for highly efficient, small-volume ultra-HTP screenings of primary cells, in areas such as neurology and
liver metastasis, to accelerate basic research, target identification and drug validation. FGENTCARD’s
major goal is to develop methodologies that integrate functional genomics tools and genetic strategies
to address major unresolved questions concerning the molecular basis of common diseases with a focus
on coronary artery disease. TargetHerpes focuses on improving tools for producing novel antivirals.
These projects have already shown a clear added value in carrying out the work at an extremely cooperative
and integrated European level, by establishing tools with international visibility, that have been developed
through close collaboration of partners, both across European countries and via international cooperation.
FP7 future actions will continue to support projects developing tools for gene expression under the FP7 priority
sub-area for HTP research.
Following the technological development in genomics, the interest in the simultaneous analysis and measure-
ments of genome-wide protein levels will be of central importance in biological studies, since proteins are the
main regulators whose concentration and modification define the cells responses to the environment.
Proteomics complements other functional genomics approaches, including microarray-based expression profiles,
systematic phenotypic profiles at cell and organism level, systematic genetics and small-molecule-based arrays.
Additionally, proteomics is set to have a profound impact on clinical diagnosis and drug discovery via the detec-
tion of protein profiles associated with disease states, since most currently used drug targets are proteins.
Tremendous progress has been made in the past years in generating large-scale data sets for protein-protein
interactions, organelle composition, protein activity patterns and protein profiles in healthy and diseased situa-
tions. Moreover, large-scale data sets will be crucial for the emerging field of systems biology. But further techno-
logical improvements, coordination of European and international proteomics efforts, as well as open access to
results are needed for the field of proteomics to realise its full potential.
Proteomics advances would not be possible without the previous achievements of genomics, which provided the
‘blueprint’ of possible gene products that are the focus of proteomics studies. Unlike the challenges faced with the
human genome projects, proteomics faces inherent challenges which deal with problems of material limitations
and variability, sample sensitivity and degradation, low to high abundance, a plethora of post-translational modi-
fications and unlimited tissue, developmental and temporal, diseased state and drug responses variations. In
addition, over of the last years, vast amounts of heterogeneous data has been generated in proteomics research
as well as different bioinformatics software and formats, a fact that creates barriers for the direct comparison
and the sharing of data.
FP6 activities
To address the current challenges and the immense potential of the proteomics field, the majority of FP6-funded
projects were oriented towards improving throughput potential, sensitivity and accuracy of detection of the
proteomes, as well as the standardisation of data. INTERACTION PROTEOME, the largest effort established
at the European level, has objectives focused on the future of the functional proteomics field, via the develop-
ment of a broadly applicable platform of innovative methods for the analyses of protein-protein interactions.
A multidisciplinary approach has been established to address different aspects of protein-protein interaction
data: their validation by cell biology, biochemical and biophysical methods; the improvement of in silico (in
italics) methods for prediction of protein interactions; and ultimately the development of a new type of public
database for protein-protein interaction data.
The ProDac CA is contributing to the international proteome standards initiative for HTP proteomics by
implementing these standards in public repositories and data submission pipelines, and demonstrating the
practical use of improved, standardised proteomics data collection and analysis to the proteomics community.
NEUPROCF, a project with a more specific focus, is further developing and applying a set of proteomics tools
for the detection of low-abundance proteins to help the study of disease phenotype (i.e. cystic fibrosis). With the
project CAMP, the new emerging field of chemical genomics has also been addressed.
FP7 activities
Establishing how networks of proteins associate in time and space to generate function is an important goal in
post-genomics research. The formation of interaction networks is essential for cellular function and requires pro-
teins to be at the right place, at the right time and in the right concentration.
To keep Europe at the forefront of technology development in proteomics research, the EC, via its Health priority,
published the FP7 second call for proposals for SME-targeted focused CPs in HTP research. Several proteom-
ics projects have been selected for funding and are currently under negotiation. Continuing the efforts, the EC
published the FP7 third call for proposals in September 2008 with the aim of developing tools, technologies
and resources for the characterisation of protein functions, to be implemented via a bottom-up approach and a two-
stage selection procedure. In this way, the scientific community will be consulted for their ideas on research projects
developing state-of-the-art proteomics research.
Further advances in proteomics techniques will help overcome bottlenecks in the investigation of protein functions
in cells, leading to a better understanding of biological processes in health and disease, and fostering European
research excellence and technological innovation.
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺMOLECULARĺIMAGINGĺ
Although we need to continue to sequence genomes and to indentify individual proteins involved in a given bio-
logical response, the ultimate challenge will be to utilise the enormous amount of data generated and to convert
this into a dynamic picture of the subcellular, cellular or whole organism level. In the dynamic cellular environ-
ment, proteins and other cellular components undergo many processes — all primarily designed to maintain
cellular function and homeostasis.
Most of the current knowledge on gene expression, regulation and delivery in mammalian systems results from in
vitro or ex vivo studies. It is worthwhile reflecting on the fact that study of a biological system over time is gener-
ally constructed from a series of data obtained from different specimens, which often fail to represent accurately
the true order of events in vivo. This situation, coupled with our inability to easily monitor multiple molecular
species simultaneously, seriously limits our ability to study cellular processes, keeping in mind that biology is
fundamentally dynamic.
Biomedical methods have elucidated many cellular pathways and continue to do so. However, the desire to capture
microsecond and nanosecond cellular changes and interactions in living cells in their natural environment, as well
as the need for high spatial and temporal specificity have led to the development of increasingly sophisticated imag-
ing technologies. These techniques are becoming more powerful with the contribution of computing power.
FP6 activities
The EC has supported FP6 collaborative projects (CPs), aiming at the development of new imaging technologies
for monitoring gene and protein expression in situ and in vivo (often in tissues or living cells and whole animals).
MOLECULAR IMAGING is an IP aiming to develop novel non-invasive imaging techniques that enable
monitoring of the dynamics of multiple molecules within living systems, and whole animals INĺVIVO.
The Tips4Cells focused project aims at further developing scanning probe microscopy (SPM); this is currently
the imaging method of choice for measuring intermolecular and intramolecular forces in biomolecules at the
single molecule level and for providing high-level information on structural details of biological samples in their
native environment. The COMPUTIS focused project is developing new and improved technologies for molecu-
lar imaging mass spectrometry (MIMS), enabling innovative methods of investigation in functional genomics,
proteomics and metabolomics, as well as investigation in cells and tissues.
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺGENEĺINTEGRATIONĺANDĺRECOMBINATIONĺ
One of the most important goals in the post-genomics era is to systematically determine the function of all genes
and regulatory sequences within living cells. The so-called reverse genetics approaches rely on the targeted
integration of artificial gene constructs by homologous recombination to delete (knock-out) or alter (knock-in)
chromosomal sequences.
The modification of the cell’s genome by methods of gene targeting has traditionally been used in modern biol-
ogy for gene function analysis and for development of tools for gene therapy. Therefore, controlled gene integra-
tion and in particular targeted integration are key technologies for the exploitation of the full function of genomic
information. Targeted gene integration also fulfils a critical role in medical research, as it allows the establishment
of animal disease models for advancing research in disease pathogenesis and treatment.
Gene targeting allows researchers to precisely modify the genetic blueprint of living cells in vivo. The mechanism
of gene integration into the chromosomes of living cells is far less known, and can occur either randomly or be
targeted by homologous recombination.
In FP6, the EC supported several focused research projects developing tools for gene integration and the study of
the mechanisms of gene integration in different model organisms.
The GENINTEG project seeks to establish a greater understanding of the mechanism of gene targeting and devel-
op new generic tools for enhancing gene integration by applying an interdisciplinary and multi-organism compara-
tive approach. TAGIP is a focused project that aims to develop gene targeting via homologous recombination as a
routine technology in plants that will facilitate the cost-efficient and large-scale production of therapeutic proteins.
The PLASTOMICS project will define the mechanisms and improve the understanding of the genes and proteins
involved in several key stages of plastid transformation and foreign proteins expression. The focused project
MEGATOOLS studies meganuclease-induced recombination; this approach could provide a practical alterna-
tive to current approaches and represents an extremely powerful tool for gene alteration.
The clarification of gene function by transgenesis is important for our understanding of biological processes
and disease pathogenesis. Therefore, investment in further developing gene integration technology promises
advances not only in basic research, but also in drug development.
ĺ2EGULATIONĺOFĺGENEĺEXPRESSIONĺ ĺ
Research into regulation of gene expression will enable scientists to decipher the functions of genes and their
protein products, and acquire a clearer picture of the complex regulatory networks that control fundamental
biological processes.
The gene expression process is of fundamental importance for all living organisms. Regulation of gene expression
refers to cellular control of the quantity and the timing of changes to the appearance of the functional product of
the gene. Most genes reside in the chromosomes located in the cell nucleus and express themselves via proteins
synthesised in the cytoplasm. The genetic information is transcribed from DNA to RNA, and then translated from
The sequence of an organism’s genome does not directly determine how the genome is used to build the organ-
ism. Buried deep in the primary code is a second regulatory code, which must also be deciphered.
To address the importance of the gene regulation in the post-genomics era, the majority of FP6-funded projects
were oriented towards the understanding of:
■ transcription regulation
■ epigenetic regulation.
The knowledge and methods developed within the FP6-funded projects will improve EU scientific competitive-
ness in the rapidly developing field of regulatory genomics, hopefully giving European scientists a head start
in the race to decipher the regulation of the genetic code.
ĺ4RANSCRIPTIONALĺREGULATIONĺ
Our genome consists of approximately 22 000 protein coding genes. However, only a fraction of these are used
in each cell. Which genes are expressed (i.e. govern the synthesis of new proteins) is controlled by the machinery
that copies DNA to mRNA in a process called transcription. In the gene expression pathway, the first regulated and
in most cases rate-limiting step is the process of transcription. This process, in turn, can be modulated by various
factors. A number of conceptual as well as mechanistic questions still need to be answered before we can attain a
complete picture of the principles employed by living organisms to control this process. One of the main gaps in our
knowledge is the limited insight we have regarding transcription regulation in the nuclear environment.
The goal of the TRANS-REG focused project is to obtain a comprehensive knowledge of the mechanism of
regulation of model genes during cell differentiation, cell proliferation and signal transduction. The consortium
is undertaking concerted efforts to develop and apply different molecular and cell biology approaches to study
the molecular characteristics.
The X-TRA-NET project develops and employs chromatin immunoprecipitation technology combined with sequenc-
ing to explore the complex transcriptional network of nuclear receptors signalling pathways and regulation. These
unique methods will be used to investigate the impact of binding site diversity on the mechanism of gene activation
with potential impact in the treatment of major diseases such as cancer, insulin resistance and atherosclerosis.
ĺ%PIGENETICĺREGULATIONĺ
The completion of the human genome has provided a wealth of information about our genetic wiring. Epige-
netics is defined as the study of the heritable changes in genome function that occur without a change in DNA
sequence. It seeks to determine how genome function is affected by mechanisms that regulate the ways the genes
are controlled. There are hundreds of different kinds of cells in our bodies. Although each one derives from the
same starting point, the features of a neuron are different from a liver cell. As cells develop, their fate is governed
by the selective use and silencing of genes. This process is subject to epigenetic factors where DNA methylation
plays an important role in all the phenomena where genes are switched on and off. Epigenetics also provides a
means by which genetic material can respond to changing environmental conditions.
Over recent years, the study of epigenetics (chromatin and/or DNA modifications not attributed to changes in
the DNA sequence but surviving across generations) has received increased attention due to its possible role in
pathogenesis and in a series of the organism’s phenotypic characteristics.
The EPIGENOME project has established a network of excellence (NoE) providing a platform for the development
of the European epigenetic research. It seeks to promote the ERA in the field, not only by means of a strong research
programme, but also by integrating and disseminating the project’s activities, including an efficient communication
infrastructure to enable internal communication of geographically dispersed teams and to foster public dialogue.
The HEROIC project advances epigenetic research with HTP technology in the context of the whole genome
to help unravel the meaning of the epigenetic code. It performs research into gene regulatory systems at the
level of the chromatin structure and nuclear organisation, employing the most extensive multidisciplinary con-
sortium ever assembled at European level. Although the chromatin immunoprecipitation (ChIP) assay plays a
crucial role in deciphering patterns of epigenetic marks that govern gene transcription, it still suffers from low
resolution and low sensitivity. The CHILL project will overcome this by developing Chromatin Immuno-Linked
Ligation (ChILL) technology resulting in a better understanding of the epigenetic code. The SMARTER project
will help in the treatment of cancers by investigating the small molecules that target histone deacetylases and
by opening up new avenues of research.
Epigenetic research is anticipated to have far-reaching implications for medicine. Using a combination of ge-
nomic tools, researchers are trying to better understand processes like DNA methylation in order to use the
information for more effective early diagnosis of complex diseases (such as cancer) and to develop innovative
treatments directly targeting the molecules involved in these processes.
ĺ3TRUCTURALĺGENOMICSĺANDĺSTRUCTURALĺPROTEOMICSĺ ĺ
The way molecules such as proteins and ribonucleic acids (DNA and RNA) interact with one another and with
other molecules (such as drugs) is determined by their 3-D structure. Understanding the 3-D structure of these mac-
romolecules is critical for the understanding of their role in complex biological processes, and is essential for drug
design. Most molecular interactions can only take place as a result of the molecules’ chemical architecture, creating
active sites where they can link together with complementary molecules or interact as a part of cellular machinery,
in order to acquire the functional state required in a living organism. In proteins, these sites depend on the way the
long chains of amino acids of which they are constituted are intricately folded to give a final 3-D structure. Most
drugs target particular protein functions, either of proteins of human origin or of a specific pathogen, and the de-
velopment of new drugs relies heavily on knowledge of the targeted protein’s structure. Compounds with potential
pharmaceutical activity can be designed and tested to determine their potential by altering the protein structure.
Structural genomics researchers are using and developing a variety of techniques to study the 3D structure of mac-
romolecules ((X-Ray crystallography, nuclear magnetic resonance or NMR, 3-D Electron Microscopy). During, the
last decade, the major bottleneck in the technological developments described above, from the stage of sample
preparation to the analysis of structural data, has been the low-throughput outcome. The techniques did not permit
a sufficiently HTP analysis of samples and the determination of the structures of the thousands of macromolecules is
still to be solved. Research effort has therefore been focused on the automatisation of many stages in the procedures
to reduce bottlenecks and increase throughput.
The concept of structural genomics arose in the late 1990s in the US and Japan as a response of the success
of HTP sequencing methods applied to whole genomes. It was anticipated that similar HTP methods could be
applied to obtain 3-D structures of all the proteins. This vision led to the investment of substantial funds into large-
scale structural genomics projects in the US (between 2000 and 2005) and in Japan. Europe was slow to enter
the area of structural genomics and proteomics, and European investment in this area has been on a consider-
ably smaller scale.
In Europe, the first large collaborative initiative in implementing HTP approaches to structural biology was
launched in 2002 (pilot FP5 IP) with the project SPINE: Structural Proteomics in Europe (www.spineurope.org).
The challenge set for SPINE was to push forward cutting-edge technologies aimed at biomedically relevant tar-
FP6 activities
The effort in structural genomics and structural proteomics activity area was substantially increased in the EU’s
FP6 Programme for RTD (2002–2006), with objectives to enable researchers to determine, more effectively and
at a higher rate than was currently feasible, the 3-D structure of proteins and other macromolecules, which is
important for elucidating protein function and essential for drug design.
Whereas, in general, the projects elsewhere have tended towards a HTP approach, which would cover an
organism, an organelle or a category of proteins, most of the European projects are oriented towards technol-
ogy development or high-value targets, in most cases associated with diseases (drug targets, viral pathogens,
membrane receptors, signalling complexes involved in neuronal development and degeneration, immunology,
and cancer).
The FP6-funded projects in structural genomics and proteomics, whose objectives, results and potential impact
are presented in this publication, cover the three main technological disciplines (X-Ray crystallography, NMR,
and Electron Microscopy), which in many cases are integrated into the same consortium for the first time.
1. Projects that are biologically focused and generate high-value 3-D structures
of proteins and complexes of fundamental and biomedical importance.
These projects aim at the following:
Furthermore, the optimisation of methods for the production of proteins is important for retrieving suf-
ficient quantities for crystallisation purposes. OptiCryst is a focused project with the goal of improving
and automating methods for protein crystallisation and the objective of increasing speed and crystallisa-
tion success rates. IMPS aims at innovative techniques for expressing, stabilising, purifying and crystal-
lising membrane proteins.
Interdisciplinary
Mature Field
Initiatives in Structural Genomics/Proteomics
VIZIER E-MeP
SPINE2-COMPLEXES
(RNA Viruses) (Membrane Signalling Pathways-
Biologically-Focused proteins)
Structures of complexes
Research FSG-V-RNA 3D-Repertoire
(viral RNA) (Large Complexes)
UPMAN (protein
Technological GeneFun (in silico
strucure prediction) misfolding-
Developments BIOXHIT aggregation) 3D-EM
(X-ray (Electron
3DGENOME Crystallography) NDDP (NMR- Microscopy)
1st call - 2002 (3D microscopy) phosphatases)
2nd call - 2003
3rd call - 2004 Coordination, Fora, FESP (Forum for NMR-Life E-Mep-Lab TEACH-SG
European Structural (coordination (Training in (Training in
4th call - 2005 Workshops, Training Proteomics) action) Membrane proteins) Structural Genomics)
IP, NoE
European FP5 foundations for European Structural Genomics:
STREP, CA, SSA
FP5 Pilot project SPINE (pilot IP 2002-2005)
Fig. 7: Steps to ERA in Structural Genomics and Structural Proteomics in FP6 (2002-2006)
FP7 activities
The future of the field relies on combining integrated structural biology with cell biology so that the atomic dissec-
tion of the cell can be reconstituted into a functional system (3-D cellular structural biology). FP7 will continue to
support projects aiming at developing new and/or improving existing tools and technologies for protein and pro-
tein-complex structure determination. Most importantly, in FP7, structural genomics projects will be implementing
The following two complementary large IPs were funded and started in the beginning of 2008.
NeuroCypres
At a funding level of `11 million, this IP focuses on channel proteins of the central and peripheral nervous system
involved in severe neurodegenerative diseases. Its main strength is its multidisciplinary approach with a focus on
biology for understanding the link between dysfunction and disease.
Figure 8 shows the runtime of current EU-funded CPs in structural genomics and structural proteomics between
2002 and 2008, including all FP6 and the FP7 first call funded projects.
This drastic change in investment implemented via the European FPs for RTD (FP5, FP6 and
FP7 first call for proposals), resulted in a major investment of approximately `120 million
allocated to Collaborative Structural Genomics projects between 2002 and 2008.
Project Acronym 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 FP
SPINE IP E13.7m FP5
BIOXHIT IP E10m FP6
3D-EM NoE E10m
3DGENOME STREP E2.2m
E-MeP IP E10.35m
VIZIER IP E13m
NDDP STREP E1m
UPMAN STREP E1.9m
GeneFun STREP E1.5m
FSG-V-RNA STREP E2.4m
3D-Repertoire IP E13m
Extend-NMR STREP E2m
HT3DEM STREP E1.8m
IMPS STREP E1.9m
OptiCryst STREP E2.3m
SPINE2-COMPLEXES IP E12m
FESP SSA E0.3m
E-MeP-Lab SSA E0.3m
NMR-Life CA E1.1m
TEACH-SG SSA E0.5m
Fig. 8: Runtime of current EU-funded collaborative research projects in structural genomics and structural proteomics
(funding period started in 2004 for FP6 projects-most projects extend well beyond 2007; funding period started in 2008 for the FP7 first call projects)
The sequencing of the human genome has revealed that our genetic material is composed of about 22 000 different
genes. Despite their morphological differences, model organisms and humans share a strong conservation of genes
as well as fundamental biological pathways. This extensive conservation has promoted the use of model organisms
as a means to study conserved processes.
However, just identifying a gene does not tell us much about its potential function in health and disease. To in-
vestigate this, it is necessary to mutate the gene in a model organism. Several model organisms are extensively
studied to understand particular biological phenomena, with the expectation that discoveries made in these
models will provide insight into the workings of other organisms. In particular, model organisms are widely used
to explore potential causes and treatments for human disease in instances where experimentation on humans
would be unfeasible or unethical.
FP6 activities
In FP6, substantial resources were invested in comparative genomics, in particular for research in rodent
models like the mouse and the rat, but also in other vertebrate models like the zebrafish and the frog. Projects
involving invertebrate models (e.g. nematodes, yeast, etc.) were been funded in FP6. Finally, bacterial and
plant functional genomics projects were also partially supported as cross-cutting activities with other FP6 fun-
damental genomics thematic areas.
ĺ-OUSEĺ
The identification of all the genes in mice and humans in the Human Genome Project has shown that about 99%
of the genes in mice have an equivalent gene (or homologue) in humans. This is important as, to date, around
5 000 diseases have been shown to be caused by an error in our genetic make-up (in our genes), for example
cystic fibrosis and Down’s syndrome. In several more complex diseases, such as diabetes, an error in the genetic
make-up is a contributory factor.
In addition, powerful conditional mutagenesis technology has been developed that currently can only be applied
in the mouse to specifically inactivate any gene in a time- and space-dependent manner. This approach allows
us to very precisely unravel the genetic networks underlying disease. All things considered, the mouse is one of
the model organism of choice for human disease research.
EUMORPHIA was the first major integrated research programme (funded at the end of FP5) on mouse re-
search that brought together a large consortium of 18 mouse research centres in 8 European countries. The
main goal of this large initiative was the development and standardisation of new approaches in phenotyping,
mutagenesis and informatics leading to improved characterisation of mouse models for the understanding of
human physiology and disease. The project delivered an extensive database of standardised phenotyping
protocols (EMPReSS) that is now widely used in many mouse laboratories across Europe (Brown S.D. et al.,
Nature Genetics, 2005, 11, 1113–20). Furthermore, this project has also played an important role in structur-
ing the research landscape in mouse research in Europe.
In FP6, building on the success of EUMORPHIA, several mouse large-scale functional genomics initiatives
(EUCOMM, EUMODIC, EUREXPRESS, and MUGEN) were funded that may be grouped as follows:
EUCOMM integrates European skills, resources, and infrastructure to produce, in a systematic, HTP way,
mutations throughout the mouse genome. A collection of up to 20 000 mutated genes will be generated
in mouse embryonic stem (ES) cells using conditional gene trapping and gene targeting approaches. This
mutant resource will be of crucial importance for health research since it will allow scientists to dissect
gene functions within a living organism (in vivo) more accurately and to mimic human disease conditions
more closely. By networking their effort at the European level with the EUCOMM project, Europeans
researchers are playing a leading role in the International Mouse Knockout Consortium that was launched
recently (Collins F.S., Cell 2007, 128, 9–13; Qiu J., Nature 2006, 444, 814–816) and which joined
EUCOMM, KOMP (funded by the National Institutes of Health) and NorCOMM (funded by Genome
Canada). FLPFLEX is a more focused project aiming to develop flexible genomic insertion cassettes
carrying modifications to allow recombinase-mediated cassette exchange of effector genes of interest.
Molecular Imaging is another project (mentioned earlier in the functional genomics tools section) which
aims to develop non-invasive imaging tools for whole animals (mice) in vivo.
EUREXPRESS and EUMODIC are both focused on phenotyping. EUREXPRESS’s main goal will be to
deliver expression patterns for 20 000 mouse genes during embryonic development and in adult tissues.
EUMODIC will phenotype in depth, using the EMPReSS standardised protocols (about 650 mutant lines)
produced from the EUCOMM project. MUGEN is another FP6 major research initiative using functional
genomics tools to analyse more that 200 mouse mutant strains showing defects in the immune systems in a
standardised way.
These projects cover a great variety of basic biological processes; several projects use predominantly
mouse as the animal model of choice.
MUGEN aims to structure and shape a world-class network of European scientific and technological
excellence in the field of murine models of human immunological diseases that will advance understanding
of the genetic basis of disease and enhance the innovation and translatability of research efforts.
The main objective of HEROIC is to make significant advances in the mechanistic questions of epigenetic
regulation, characterise the epigenetic modifications that occur, and then understand the implications for
gene expression in different cell types. The approach focuses on the use of HTP-enabling technologies on
predominantly primary and established mouse cell lines, particularly ES cells.
The majority of the projects funded under the areas on multidisciplinary approaches to basic biological
processes (see Part B,Chapter 7) are either using established mouse models or creating novel mouse models
to understand health diseases. One example is the FunGenES consortium, which addresses fundamental
issues of stem cell biology differentiation and functional genomics, pursuing an integrated strategy based
on cultured mouse ES cells. Another, the EUROHEAR IP develops novel mouse models to understand the
mechanisms of hearing deficiencies.
Along with the research initiatives, the EC has financed two CA projects: PRIME and CASIMIR. The aim of
PRIME is to build on existing national and European mouse research programmes, resource centres and
infrastructures by focusing and integrating them, rather than establishing new programmes. The long-term
aim is to establish mechanisms to define future research policies and directions in a coordinated manner
across Europe. CASIMIR focuses on coordination and integration of databases set up in support of FP5
and FP6 projects containing experimental data, including sequences, and material resources such as
biological collections, relevant to the use of the mouse as a model organism for human disease.
MUGEN EUROHEAR
FunGenES HEROIC
Biologically (mouse models
(mouse ES cells (Epigenetics in
(mouse models
Focused Research for immunological for hearing
differentiation) Mouse ES cells)
diseases) deficiencies)
EURExpress
EUMODIC
(high-throughput
Phenotyping in situ
(European mouse
Disease clinic)
hybridisation)
IP, NoE
FP5 foundations for European Mouse Functional Genomics
European
Pilot project
Programme: EUMORPHIA (pilot IP 2002-2005) on
STREP, CA, SSA standardised phenotyping protocols
ĺ2AT
Europe has a large community of researchers using the rat as a model. Indeed, over the last 50 years, the
rat has also intensively been used by physiologists to investigate molecular determinants of diseases such as
diabetes. The availability of the rat genome sequence (since December 2004) and genome-scale technologies,
along with the ability to clone fertile adult rats, has substantially advanced the potential for functional genom-
ics research in the rat model.
The EURATools IP draws together leading European researchers in rat genetics, pharmacology, toxicology, dis-
ease pathophysiology, and genome biology and informatics. The central aim of this project is the development
of integrated genome tools that will generate knowledge that can be translated into improvements in healthcare
for highly prevalent diseases in the EU. Besides scientific excellence, EURATools is expected to have a strong
European structuring effect in the rat research community.
In addition, two smaller-scale projects, MED-RAT and STAR, were also funded in FP6. These two projects are
complementary to the EURATools project: one is developing new tools to generate transgenic and knock-out rat
models (MED-RAT) while the other is generating a SNP and haplotype map for the rat model (STAR).
Furthermore, for developmental biologists, the zebrafish model offers additional advantages. Indeed, the devel-
opmental processes can be easily observed in the fish since the embryo develops outside the mother body and
is also fully transparent. ZF-MODELS IP aims to utilise the zebrafish model to harvest large datasets on gene
functions underlying development and disease. Fish with genetic disorders corresponding to human diseases are
produced by chemical mutagenesis (forward genetics) and targeted knock-out (reverse genetics) and are phe-
notypically characterised. These disease models will aid clinical researchers and the European pharmaceutical
industry in the development of new therapies. This project will also contribute to improving basic knowledge of
human development, since key genes involved in development are often reactivated in adult life in many con-
genital diseases and cancers.
Furthermore, the zebrafish embryo model also shows great potential to be incorporated into preclinical drug
screening pipelines. ZF-TOOLS aims to develop a case study for an anti-tumour drug screening system, based
on implantation of fluorescently labelled tumour cells into zebrafish embryos. This system allows for the powerful
combination of visual monitoring with HTP analysis of expression of marker genes with a predictive value for
tumour progression or for defence responses to developing tumours.
ĺ/THERĺMODELSĺ
The EC is also supporting functional genomics research projects in other model organisms including Xenopus
laevis (X-OMICS) and C. elegans nematode (NEMAGENETAG). Under the Systems Biology umbrella, the
EC is also supporting a large IP (AGRONOMICS) on leaf development in Arabidopsis thaliana and a large
IP (BaSysBio) in Bacillus subtilis. These projects are also cross-cutting in nature, relating to other FP6 thematic
priorities, in particular with Priority 2, related to Food Safety.
Importantly, an essential part of the thematic sub-area ‘Multidisciplinary functional genomics approaches to study
basic biological processes’ is devoted to model organism research used as tools to understand a particular basic
biological process. These projects are presented in a separate section in the current publication.
In conclusion, between 2002 and 2007, the EC’s FPs (FP5, FP6) provided more than `150
million for collaborative research projects on model organisms, such as mouse, rat,
zebrafish, plant, nematode worm and bacteria. These projects are playing an important role in
structuring the research landscape in Europe and creating the knowledge base to understand health and
disease. Furthermore, they are generating important and freely available data and/or animal resources that
will catalyse progress in biomedical research.
FP7 activities
In FP7, support of research on model organisms continues, and considering that FP6 funded several projects
in rodent models, we have proposed calls for proposals on establishing consortia on genome-wide association
studies in non-rodent mammalian models that develop diseases analogous to those seen in humans.
At the beginning of 2008, the EC launched the `12 million IP LUPA, which aims at elucidating the molecular
basis of common complex human disorders using the dog as a model system. This project brings together ex-
perts in genomics, the world’s leading scientists in complex trait genetic analysis, and interconnects the major
veterinary centres of Europe, utilising HTP molecular tools. It should also be emphasised that particular attention
is being paid to following strict national guidelines for animal welfare.
A policy workshop was organised by the Genomics and Systems Biology unit in the Health Directorate in March
2007, in cooperation with other funding agencies, (including, the US National Institutes of Health and Genome
Canada), to explore the future research needs in the field of mouse functional genomics. The recommendations
of that workshop, which brought together the world-leaders in the field, also served as a foundation to reflect
on future FP7 activities in the area. In the FP7’s third call for proposals, published in September 2008, the EC
proposed a bottom-up approach, implementing (for the first time in the Health priority) a two-stage selection
procedure, to attract proposals on large-scale functional genomics efforts in multicellular model organisms. The
expected impact is to continue progressing in the understanding of the function of all human genes, their complex
interactions, and their role in disease.
Project Acronym 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 FP
EUMORPHIA IP E17.3m
EURExpress IP E10.8m
MUGEN NoE E11m
FLPFLEX STREP E1.7m
EUCOMM IP E10.3m
PRIME CA E0.8m
EUMODIC IP E12m
CASIMIR CA E1.3m
STAR STREP E2.4m
MED-RAT STREP E1.6m
EURATools IP E11m
ZF-MODELS IP E12m
ZF-TOOLS SME-STREP E1.7m
TP Plants SSA E0.56m
NEMAGENTAG SME-STREP E1.8m
X-OMICS CA E0.8m
LUPA IP E11.9m
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Fig. 10: Runtime of current EU-funded collaborative research projects in model organisms
(funding period started in 2004 for FP6 projects-most projects extend well beyond 2007; funding period started in 2008 for the FP7 first call projects)
ĺ0OPULATIONĺGENETICSĺANDĺBIOBANKSĺĺ
Common diseases of major public health importance are phenotypically complex, with many having a heritable
component. Population genetics approaches are used to characterise complex diseases and associated pathophysi-
ological states in respect to the genetic and environmental determinants involved. An important element of popu-
lation genetics research is the study of the genetic variations and/or mutations that are correlated to the healthy
and diseased phenotype. The estimated 22 000 protein-encoding genes are calculated to contain myriad possible
variations, called polymorphisms, which increase the complexity of our genes. The human genome comprises about
3 x 109 base pairs of DNA, and the extent of human genetic variation is such that no two humans, even identical
twins, will be genetically identical. The amount of genetic variation is about 0.1%, meaning that about 1 base pair
out of every 1 000 will be different between any 2 individuals. Some of these variations determine physical char-
acteristics, but others can determine the susceptibility to certain diseases, or the response to drug therapies.
Access to databases containing genotypic, clinical, and environmental and lifestyle information on individuals,
along with corresponding clinical samples/specimens (biobanks), are an essential component for population genet-
ics research. The systematic collections of genetic material and other relevant information on individuals, namely
biobank collections, make it easier for researchers — using HTP analytical tools for monitoring DNA variations
combined with powerful bioinformatics — to systematically search for links between gene variation and disease.
In several European countries, a multitude of national and regional population and disease-oriented biobanks
have been systematically collected for decades via the national healthcare systems, representing a unique
European strength. Significant advantage could be gained by pooling the resources already available or
under construction. This could give researchers access to greater cohort size and data sets, so that the re-
search outcome from associations’ studies between genotype, environment, and lifestyle at individual and
population level could lead to greater statistical significance and prediction. The lack of standardised and
quality-controlled protocols for data and sample collection, storage, retrieval, analysis and access, as well as
the diversity of national legal regulations, have created a great deal of fragmentation and created obstacles
for collaboration at European level. It would make an enormous difference if the protocols involved in human
population genetics research at national level could be harmonised to become representative and accessible
at European and international level.
Building the ERA in population genetics research via a coordinated and collaborative approach will address the
existing bottlenecks and would pave the way for advances in biomedicine and improvement of the public health.
The EC, recognising the power of population-based approaches in the study of genetic susceptibility for disease,
has funded a number of networking activities and collaborative research projects between 2002 and 2008.
In Europe, the first large collaborative initiative on genetic epidemiology on common diseases utilising samples
from large- and medium-sized population biobanks and involving cross-border transfer of data and samples was
launched in 2002 (pilot FP5 IP) with GenomEUtwin (www.genomeutwin.org). The main objective for Genom-
EUtwin was to perform genome-wide analyses of European twin and population cohorts with the aim of identify-
ing genes predisposing the carrier to common diseases. During the four-year period, the partners harmonised
and integrated the study cohorts’ data (a combined cohort of 850 000 twins and a cardiovascular diseases
cohort of 160 000 volunteers). Genome-wide studies have the potential to systematically identify the contribu-
tions of common genetic variants to human disease. This unique project has provided the basis for the detection
of small genetic infuences on common diseases, which may not be detected in small-scale family studies. Impor-
tantly, the project has developed an Ethics Manual defining policies for the transfer of data and samples between
countries. GenomEUtwin is a cornerstone of European genetic epidemiological research, because it paved the
way for harmonisation of collected data, easy access to available data by creating a unified database structure
and genome-wide analysis of the existing cohorts.
FP6 activities
The success of the GenomeEUtwin project, and its catalytic effect on the area, led to new CPs in FP6. These
projects are taking full advantage of specific population cohorts available in Europe for determining the re-
lationship between gene function and health or disease. These projects may be classified into the following
general categories.
These projects bring together the critical mass to catalyse the development of techniques and technologies
for population genetics research.
MOLPAGE is an IP that develops and validates a range of ‘-omics’ technology platform tools (metabo-
nomic, genomic, proteomic) for molecular phenotyping in large epidemiological studies. These tools will be
used for identification of biomarkers, prediction of disease, and risk determination or response to therapy.
The consortium develops and disseminates standards for the collection, processing and storage of biologi-
All these projects perform large-scale studies on genetic epidemiology on common diseases and related
traits, utilising samples in large- and medium-sized biobanks and involving cross-border transfer of data
and samples.
The EUROSPAN focused project has the objective of quantifying genetic variation in established diseased
genes across population cohorts in Europe, with the goal of identifying novel disease variants. It will cre-
ate a large database of phenotypic and genotypic data from genetic isolated populations and will thus
improve European competitiveness in gene discovery.
GenOSept is a STREP which uses a multidisciplinary fundamental genomics approach to examine genetic
predisposition to sepsis by harmonising HTP genotyping and quality control between major European centres.
The EC is also financing several CAs (such as PHOEBE and IMPACTS), as well as SSAs (such as DanuBiobank
and EUHealthGen). PHOEBE promotes harmonisation of epidemiological biobanks in Europe. IMPACTS
coordinates the standardisation of tissue archives. EUHealthGen organised a Wellcome Trust/EU EC con-
ference (‘From Biobanks to Biomarkers’) to enable dialogue on the potential of human population genetics
research. The aim of Danubiobank is to establish a biobank foundation for ageing disorders by networking
universities, teaching in hospitals, developing prevention programmes and clinics along the Danube River, via
the organisation of workshops and conferences.
On the whole, these projects have the following aims: to exchange information on research biobanks in
Europe and beyond; to standardise and harmonise existing protocols for the acquisition, management and
analysis of data and samples from different sources; to develop common quality assurance schemes; and
to standardise approaches to ethical and legal issues.
By networking existing national capacities, FP6-funded projects have provided the critical mass to catalyse the
development of techniques and technologies for population genetics and to conduct large epidemiological stud-
ies. Together, these projects will enable researchers to better understand the ways in which interactions between
genes and environmental factors are involved in the causes of common diseases and to determine the influence
of specific genetic variations on the development or severity of these diseases.
FP7 activities
The FP7 Health theme has several objectives, one of which is to integrate the vast amounts of genomics, epide-
miological and biological data with a view to translating this data into the understanding of major diseases and
the ultimate development of new preventive, diagnostic and therapeutic methods. That is why population genet-
ics and biobanks research aiming to develop tools and harmonisation principles is essential in FP7.
In the future, the integration of traditional population epidemiological genetic studies with HTP ‘-omics’ tools
(genomics, transcriptomics, and metabolomics) and bioinformatics as an essential component, is expected to
tremendously boost the field of population genetics.
With this in mind, in the FP7 first call for proposals under the HTP research activity area, the EC funded a large scale
integrating project to develop groundbreaking techniques for DNA sequencing and genotyping, which is expected
to increase the efficiency and cost of existing tools and lead to wider applicability in the clinical environment.
The READNA project, with `12 million of funding, focuses on next-generation nucleic analysis technologies and
devices. The tools developed should increase the sensitivity, rapidity and efficiency of existing tools for sequenc-
In FP7’s first call for proposals, the large-scale data-gathering activity area supported two highly complementary
projects (started in 2008) for performing molecular epidemiological studies in existing well-characterised Euro-
pean population cohorts, with the objective of identifying candidate susceptibility genes to multifactorial diseases
by integrating genome-wide association studies and the advances of ‘-omics’ developments.
The ENGAGE project, with `12 million of funding, sets as its main objective the integration of the results from
many large-scale genetic studies underway in Europe and Australia, and the identification of novel disease-
and trait-susceptibility variants for multifactorial diseases. The scale is large, with more than 650 000 DNA
samples from various cohorts involved; the focus is primarily on cardiovascular and metabolic diseases, but
can be expanded to other common disorders.
The HYPERGENES project, with `10.2 million in funding, aims to dissect complex genetic traits using hyper-
tension as the disease model. The consortium will identify, by means of a whole genome association approach,
genes contributing to essential hypertension (EH) and to EH-associated target organ damage, utilising well-
characterised European cohorts. A combination of the most up-to-date methods of genomics, molecular genetics,
molecular epidemiology and bioinformatics, together with learning-based modelling of the data, is expected to
produce a disease model.
To keep Europe at the forefront of technology development in population genetics and biobanks research, the EC
published the third FP7 call for proposals in September 2008, via its Genomics and Systems Biology programme;
a bottom-up approach via a two-stage selection procedure was implemented for the first time in the Health priority.
In the activity area of HTP research, the scientific community is invited to submit proposals for large integrating
projects on the following topics:
The projects are expected to accelerate epidemiological studies and biomarker discovery by increasing
the molecular analysing capacity of biobanks, and will deliver high-quality and reproducible data set to
enable standardised approaches for large-scale biobanks.
In the activity area of large-scale data gathering initiatives, the FP7 third call for proposals invites proposals on
the following topics:
The projects should aim at characterising genetic variation in populations from different regions and ethnic
minorities in Europe, involving normal and/or disease phenotypes. A large-scale comparative study of ge-
netic variation in human populations in Europe is expected to facilitate ongoing and new epidemiological
studies, and fill in the information gaps on genetic variability in healthy and/or disease phenotypes.
The projects should implement multidisciplinary functional genomics approaches (e.g. sequencing, tran-
scriptomics and/or epigenetics) to characterise in detail a large number of human cancer tumour samples,
so as to identify molecular determinants that contribute to human oncogenesis. They should establish the
standards and norms on the manipulation and storage of tumours samples, thereby facilitating the compari-
son between different data sets.
Recognising the power of population-based approaches in the study of genetic susceptibility for disease, the
EC’s FPs for RTD provided more than `60 million to collaborative research projects in this
area between 2002 and 2008 (see fig.11 representing the steps towards the ERA in population genet-
ics research). In future calls, the Health theme will continue supporting this area, which will allow the EU to
develop and maintain a leading global position in genetic epidemiology and population genetics.
ENGAGE HyperGenes
Genetic epidemiology GenOSept (genetic
(genetic epidemio- (genetic EUROSPAN
predisposition
of common diseases logy-Common epidemiology- (genetic variation)
sepsis)
diseases) hypertension)
MolPAGE READNA
(molecular (sequencing/genotyping
Technological Developments
phenotyping tools) technologies)
Fig. 11: Steps to ERA in Population Genetics and Biobanks in FP6 (2002-2006) and FP7 first call projects
ĺ"IOINFORMATICSĺ ĺ
As we move towards understanding biology at the systems level, access to large data sets of many different types
has become crucial. The data obtained from such technologies (such as genome-sequencing, microarrays, proteom-
ics and structural genomics) have provided ‘parts lists’ for many living organisms, and bioinformatics provides the
systematic cataloguing and interpretation of this data. Researchers are now focusing on how the individual compo-
nents fit together to build systems. The hope is that scientists will be able to translate their new insights into improving
quality of life. The functional genomics HTP revolution is generating a vast amount of data. There is an ongoing (and
growing) need to collect, store and curate all this information in ways that allow its efficient retrieval and exploita-
tion. By making these data available to the academic and industrial research communities in an accessible and
usable form, bioinformatics research ensures that the potential for genomics and health research is maximised.
FP6 activities
The FP6 objectives for the field of bioinformatics were to enable researchers to access efficient tools for manag-
ing and interpreting the ever-increasing quantities of genome data, and for making it available to the research
community in an accessible and usable form.
The foundations for meeting these challenges were laid in FP5, especially with the major large-scale IP TEM-
BLOR, which supported the development of major databases, including those for protein structure and sequence,
protein-protein interaction, gene expression and integration of this and other data. The capabilities established
and strengthened by TEMBLOR brought Europe to a level similar to that of other major world centres in the key
areas of life sciences research.
In FP6, an ERA has been established in bioinformatics, building on the foundations in FP5. This bioinformatics
ERA forms the basis for a wide range of applications for health research, and will be a key element in a future
ERA in systems biology, already under development in FP6 as well.
In bioinformatics, BIOSAPIENS has created a European Virtual Institute for Genome Annotation, bring-
ing together the best laboratories in Europe, including informaticians and experimentalists. The institute has
greatly improved bioinformatics research in Europe by providing a focus for annotation, and by organising
European meetings and workshops to encourage cooperation, rather than duplication of effort. The Institute
has established a permanent European School of Bioinformatics, to train bioinformaticians and to encourage
best practice in the exploitation of genome annotation data for biologists. The tools developed have already
been applied to gain important insights into the mechanisms of genetic mutation in major diseases such as
HIV/AIDS and Down’s syndrome.
The EMBRACE NoE integrates the major databases and software tools in bioinformatics in Europe by creating a
bioinformatics computer grid for easy and integrated data access, analysis and services. The integration efforts
are being driven by an expanding set of test problems representing key issues for bioinformatics service providers
and end-user biologists. As a result, groups throughout Europe will be able to use the EMBRACE service interfaces
for their own local or proprietary data and tools. ATD aims to understand the mechanisms that are responsible
for the formation of transcript isoforms on a genome-wide scale by creating a value added database of alternate
transcripts from human and model species.
Finally, ENFIN is connecting bioinformatics and wet-lab capabilities with a Europe-wide integration of computa-
tional approaches in systems biology. Computational work includes the development of a distributed database
infrastructure appropriate for small laboratories and development of analysis methods including Bayesian net-
works, metabolite flux modelling and correlations of protein modifications to pathways. ENFIN will deliver a
platform for database provision of diverse biological data, integrated analysis tools, guides for wet laboratory
utilisation, and ‘best practice’ guidelines for systems biology.
The development of computational biology and integrated bioinformatics databases of diverse ‘-omics’ data is an
essential component for the successful implementation of systems biology approaches. Several systems biology
projects funded in FP6 (see following section) are focused on the development of computational tools. There are
several characteristic examples: EMI-CD is developing a software platform connecting several modules neces-
sary for the in silico modelling of complex disease processes, while COMBIO combines a unique group of ex-
perimentalists, bioinformaticians and simulation groups in order to gain detailed understanding of key processes
like the P53-MDM2 regulatory network. Also, COSBICS is establishing and applying a novel computational
framework to investigate cellular signalling pathways and subsequent target gene expression. The DIAMONDS
project aims to demonstrate the power of a systems biology approach in the study of the regulatory network
structure of the most fundamental biological process in eukaryotes: the cell cycle, in different species.
FP7 activities
Continuing the efforts to strengthen the ERA in bioinformatics, in the FP7 first call for proposals under the HTP
research activity area, the EC funded a large scale integrating project to unify human and model organism ge-
netic variation databases; this is expected to achieve effective linkage between databases and would facilitate
analysis in population genetics studies.
The GEN2PHEN project, with `12 million level of funding, implements an integrated approach towards unifying
To keep Europe at the forefront of bioinformatics developments, the EC, via its Genomics and Systems Biology
programme, published the third FP7 call for proposals in September 2008, implementing a bottom-up approach
via a two-stage selection procedure for the first time in the Health priority.
In the activity area of HTP research, the scientific community is invited to submit proposals for large IPs on the
following topic.
In summary, between 2002 and 2008, the EC’s FPs for RTD provided approximately `75 mil-
lion to collaborative research projects in the area of bioinformatics. Before FP6, although there
was a strong European core at the European Bioinformatics Institute, there were a wide range of databases
and capabilities scattered across Europe with suboptimal access and interaction. By the end of FP6, databases,
services, analysis tools, and scientific research were strengthened locally and linked together at European level
to produce highly coordinated resources in support of biology and health-related research, a fact that has greatly
increased our understanding of the wealth of data being generated in Europe and the rest of the world.
Bioinformatics Databases,
-ATUREĺ&IELD
Computational tools for Systems Biology
Fig. 12: Steps to ERA in Bioinformatics in FP6 (2002-2006) and FP7 first call projects
The full potential of systems biology research has not yet been achieved in Europe, because basic databases and
research methods have not yet provided the entire basis needed to fully apply a systems approach. The approaches
planned in FP7 should allow us to overcome the future challenges in bioinformatics and computational biology.
ĺ-ULTIDISCIPLINARYĺFUNCTIONALĺGENOMICSĺAPPROACHESĺ
ĺ TOĺBASICĺBIOLOGICALĺPROCESSESĺ
The different approaches to functional genomics described in the earlier sections — gene expression, proteom-
ics, structural genomics, model organisms and population genetics and bioinformatics — provide researchers
with an extremely powerful multidisciplinary ‘toolbox’ which they can use to study and manipulate fundamental
biological processes.
By picking the most appropriate genomic tools, or combination of these tools, researchers are developing inno-
vative ways to study the basic understanding of cellular processes, by revealing the function and interactions of
cellular components in health and disease. The multidisciplinary approaches provide opportunities to view these
processes from different angles and gain new insights into the underlying cellular functions.
Diseases are often the result of important biological processes dysfunctioning, either because of external stimuli,
such as pathogens or environmental factors, or because of inherited or acquired gene mutations resulting in
incorrectly coded gene products unable to perform the appropriate cellular function. By understanding normal
cellular processes in organisms as diverse as micro-organisms, plants and animals, researchers will be able to
manipulate the cellular processes involved in disease, enabling therapeutic advances.
In FP6, this research sub-area funded projects implementing innovative and multidisciplinary approaches of func-
tional genomics to study basic biological processes in health and diseases. A series of large-and medium-scale
transnational projects were supported in FP6, where the main goal is to develop innovative ways to understand
basic biological processes such as transcription regulation, DNA repair, cell cycle, epigenetics, hearing and vision
processes, immune system, intra- and inter-cellular signalling, and developmental processes. The innovation is a
result of the integration of the most appropriate multidisciplinary functional genomics tools; in this way we can gain
new knowledge on the complexity of the underlying mechanisms of life that constitute the footprint of a physiologi-
cal and/or pathological situation.
■ RNA biology
■ chronobiology
In FP6, between 2002 and 2006, the EC provided approximately `220 million to collabora-
tive research projects in the area of multidisciplinary approaches for fundamental biologi-
cal processes. All these European efforts have created the critical mass that will boost European excellence
in the respective fields by increasing integration and reducing fragmentation. It is important to mention that
even though the projects are focused on fundamental biology, for the first time several of them are integrating
basic biologists, clinical scientists and industry (including SMEs) where appropriate, to facilitate the transfer
of basic knowledge to clinical applications. Several projects are improving functional genomics tools for the
genome-wide understanding of gene function that would be applicable in all areas of cell biology. Training
courses in multidisciplinary expertise of the next generation of biologists has been implemented in several,
mostly large-scale projects. Importantly, the issues of setting up standard operational procedures on method-
ologies and data collection, and the creation of integrated bioinformatics databases have been addressed
— the latter being an essential element of collaborative effort in Europe.
In summary, the FP6 projects have already generated a comprehensive list and map of the multiple set of genes
and proteins related to a basic biological process in normal and/or pathological situations. Indeed, major
discoveries on novel gene functions have already been made that have resulted in high-level publications by
collaboration of various laboratories, previously working in isolation. Most importantly, these projects have
played an important role in integrating the research community in Europe, thereby increasing their visibility
Multidisciplinary Initiatives
-ATUREĺ&IELD
for understanding basic biological processes
Tissue/organ EuTracc
EUROHEAR EureGene (kidney ESTOOLS
Development and disease, (transcriptional
(Hearing process development (hES
regulation
Stem cell biology and deficiencies) and disease) differentiation)
in ES cells)
MAIN SIRROCO
Biological pathways
Chronic EndoTrack (Small
and signalling DNA Repair
inflammation (endocytosis) regulatory
RNAs)
1st call - 2002
2nd call - 2003
In silico tools, BIOSAPIENS
3rd call - 2004 EMBRACE
Integrated bioinformatics (Human Genome (Bioinformatics
4 call - 2005
th
IP, NoE
Tools and technologics Basis for advances in post-genomics era: High-throughput
CA, STREP for ”-omics” Tools for Proteomics, transcriptomics, model organisms, imaging
The FP6 investment constitutes the largest programme ever (in Europe and worldwide) that addresses fundamental
biology in such a multidisciplinary collaborative way, implementing state-of-the-art functional ‘-omics’ approaches.
However, it must be recognised that cellular components interact in subtle and complex ways, even in the simplest
organisms. The understanding of the enormous complexity of the interacting gene networks that are responsible for
most biological processes will require integrative and quantitative forms of analysis of diverse data. It is important to
emphasise that the ‘multidisciplinary approaches to basic biological processes’ action line, has already provided a
richness of large-scale ‘-omics’ data that constitutes the foundation for future systems biology initiatives in Europe.
ĺ"IOLOGICALĺPATHWAYSĺANDĺINTRACELLULARĺANDĺEXTRACELLULARĺSIGNALLINGĺĺ
Cellular signalling helps govern basic cellular activities and coordinates cellular function. A cell’s ability to re-
spond correctly to its surrounding environment is the basis of normal cellular growth and tissue homeostasis, as
well as development and repair. Dysfunctions of the transmission and process of signalling within the cell may
result in many diseases. An improved understanding of the basic biological pathways involved in intracellular
and extracellular signalling will lead to more effective therapies for these diseases.
In general, the FP6 projects funded in this broad sub-area could be classified into two groups: those focusing on
basic biological processes in healthy conditions, and others focusing on disease.
MITOCHECK involves research into the regulation of mitosis and into the mammalian cell cycle, ab-
normalities of which can contribute to cancer. The project applies cutting-edge technologies: the use of
RNA interference genome-wide screens to identify in a systematic manner (functional genomics) all genes
involved in mammalian cell-cycle, and proteomics approaches to identify novel protein complexes and
phosphorylation sites. A web-based database is created with such information as, the list of genes required
for mitosis, the sub-unit composition of mitotic complexes, and genome-wide RNAi screens phenotypic data
that will provide a valuable source of information to the whole cell biology community.
The RUBICON NoE focuses on the better understanding of post-translational modifications of proteins by
ubiquitination. It will establish the link to diseases such as infectious and inflammatory conditions, cancer,
and neurodegenerative disorders. This goal is achieved by applying multidisciplinary functional genomics
to elucidate the functions of genes and gene products, and by defining the regulatory networks controlling
ubiquitination.
The EndoTrack project aims at gaining conceptual advances into the signalling function of growth factors
from an unconventional perspective, namely by exploring the role of endocytic trafficking in the modula-
tion of signalling and gene expression regulation. It further aims to translate such basic knowledge into
novel opportunities for the development of a new generation of tools to combat diseases like cancer, and
cardiovascular, metabolic, and infectious and neurodegenerative diseases
The PEROXISOMES project, using cutting-edge proteomics tools, identifies and characterises the func-
tions of novel peroxisomal proteins and establishes a catalogue of peroxisomal proteins in human liver,
kidney and brain. The consortium will evaluate the role of peroxisomes as modulators or modifiers of dis-
eases of complex inheritance, such as cancer and neurodegenerative disorders.
TRANSDEATH will investigate the functional relationships between the different forms of programmed
cell death by using appropriate models. These mechanisms will then be used to understand corresponding
types of cell death in mammals, and particularly in humans.
The MAIN project is identifying and characterising the molecular mechanisms underlying chronic inflam-
matory responses and will produce cutting-edge technological approaches for use in cell migration. It
primarily studies the migration of leukocytes from the bloodstream into inflamed tissues, and their local ac-
tivation by inflammatory substances and pathogens. A bioinformatics database is being created, enabling
rapid data retrieval and analysis, and cross-correlation of functional genomic and functional proteomic
data, facilitating biological hypothesis-making and ‘systems’-level investigations.
Aneuploidy is the term used to describe the abnormal copy number of genomic elements. The ANEU-
PLOIDY project is studying the phenotypic consequences of gene dosage imbalance in humans at cellular
and organism level, by focusing on two prototype human model phenotypes: trisomy 21 and monosomy.
The project will allow the identification of genes and biological pathways potentially involved in new aneu-
ploidy syndromes.
The DNA REPAIR consortium is using an integrated multidisciplinary approach to improve understanding
of DNA damage response and repair systems in living organisms. Genomics tools are used to identify new
components of DNA damage response pathways. The project will extrapolate the findings from model
organisms to humans, by the investigation of cells from patients suffering from genome instability, cancer
predisposition and premature ageing syndromes.
WOUND will identify evolutionary conserved genes and major signalling pathways involved in epithelial
fusion and wound healing, using model systems.
The project STEROLTALK has undertaken a systematic post-genomic evaluation of cholesterol home-
ostasis and its cross-talk to drug metabolism and will contribute towards understanding the effects and
side-effects of hypolipidemic therapy and combined therapies.
All the projects described in this section have set very ambitious and technically challenging objectives which
clearly exceed the capacity of a single laboratory. The combination of a critical mass of excellent European
researchers with a readiness to develop new concepts and highly innovative methods as part of European con-
sortia has stimulated a European corporate identity in their respective fields and is expected to greatly reinforce
competitiveness. To overcome the duplication of efforts in the production of research tools and data, the majority
of the projects have established shared databases to include ‘-omics’ data which are shared between collabora-
tive laboratories. The availability of state-of-the-art HTP technologies is currently restricted to a relatively small
number of laboratories at larger institutions. All these projects have promoted access to advanced technology.
The development of these technologies, as well as the integration of industry and SMEs in most of the projects,
further facilitates the transfer of basic knowledge to future commercial applications.
ĺ4ISSUEĺANDĺORGANĺDEVELOPMENTĺHOMEOSTASISĺANDĺDISEASEĺ
FP6 has built a strong basis by funding several projects applying multidisciplinary ‘-omics’ approaches to under-
stand the molecular pathways and identify novel genes involved in tissue and organ development, degeneration
and disease. All projects apply functional genomics approaches and bring together multidisciplinary expertise
in the same consortium for the first time, and several of them are validating the knowledge produced for devel-
opment of gene and stem cell therapies. The focal point for most of these projects lies in fundamental research.
However, the involvement of clinical expertise, the use of disease population cohorts and industry (including
SME) involvement, promises rapid translation of the basic knowledge to clinical applications.
The MYORES NoE integrates the work of European laboratories previously working in isolation. The
project aims at identifying the genetic determinants of muscle normal development, degeneration and dis-
ease, and at developing technologies for HTP screening in order to isolate novel molecules and rapidly test
their suitability for muscle function and repair in animal models. The creation of the MyoBase database as
a main integrating activity will become the main source of information in muscle biology.
The aim of EVI-GENORET is to understand the fundamental molecular and cellular biology of the retina,
of its development and of the way it is perturbed by genetic mutation, environmental factors and age.
The project integrates population genetics, clinical and experimental phenotyping, molecular genetics
approaches, and HTP transcriptomics and proteomics analysis for the pathophysiology of the retina. The
creation of a state-of-the-art bioinformatics database that will integrate diverse ‘-omics’ data with clinical
data it is expected to accelerate diagnosis, disease screening, drug target evaluation and the development
of new therapeutic strategies for inherited and age-related retinal diseases.
The EUROHEAR IP has two closely interrelated objectives: to provide fundamental knowledge on the
development and function of the inner ear and to identify the molecular effects underlying hereditary hear-
ing impairments, including presbycusis. The involvement of hearing-impaired individuals and their families
in research is essential for the understanding of normal and abnormal auditory function. The EUROHEAR
project demonstrates vigorous cross-disciplinary expertise with strong interaction between human and ani-
mal models geneticists, development of biophysical and bioimaging techniques combined with functional
genomics, as well as a sound inner-ear training programme for young European scientists.
All of the above projects, representing an investment of more than `60 million, constitute the most coordinated
and integrated approach in Europe and internationally in the fields of kidney, inner ear, retina, muscle and lym-
phatic tissue health and disease.
All the above projects are developing standardisation of protocols, and several of them standard operating pro-
cedures facilitating the cross-comparison of results between geographically isolated laboratories. Several of them
are developing a strong bioinformatics database that for the first time will integrate diverse data existing in differ-
ent laboratories to be shared and analysed by members of the consortia in collaboration. An advantage in these
fields is access to large-scale population cohorts as well as access to HTP genomics and genetic platforms.
Given the genetic complexity of different organs and tissues, the cooperation between the European groups is
expected to be instrumental both in terms of resource sharing and complementary expertise. These consortia by
uniting their efforts, have created a structure unequalled elsewhere.
Disorders affecting normal organ and tissue function have an impact in the quality of life of large populations and
have a serious economic impact on the European economy. The knowledge produced will contribute strategies to
combat common and rare diseases as well as inherited and age-related diseases related to organ development
and degeneration, and to identify novel disease genes and novel targets for diagnosis and therapy.
In fundamental genomics and under the area in which multidisciplinary approaches are applied to basic biologi-
cal processes, the EC funds several projects with the aim of generating knowledge on the fundamental processes
governing stem cell differentiation in human and model organisms. If we can learn more about this fundamental
process, we might be able to reprogramme the body’s own cells, for example, to replace diseased or damaged
tissue. Various sources of stem cells are studied and compared, including ES cells, adult stem cells and induced
pluripotent stem (iPS) cells originating from somatic cells.
FUNGENES applies multidisciplinary approaches with an emphasis on microarray expression analysis to mouse
ES cells that are in a state of self-renewal or that have been induced to differentiate in various tissues of the three
major differentiation pathways. It delivers a gene expression atlas on the genetic pathways for cell differentiation
into heart cells (cardiomyocytes), nerve cells (neurons), smooth muscle cells, vascular endothelial cells, fat cells
(adipocytes), liver cells (hepatocytes) and insulin-producing cells of the pancreas. The data are analysed by meth-
ods of bioinformatics to produce new knowledge regarding genetic pathways, to identify novel genes that are
involved in different aspects of development, and lastly to validate the candidate genes by genetic engineering
of mouse ES cells. The project is expected to have an impact on future novel therapeutic strategies for diseases
including cancer, liver disease, diabetes and cardiovascular and neurodegenerative diseases.
ESTOOLS applies multidisciplinary genomic techniques and genetic tools to uncover the basic mechanisms con-
trolling the choice that human ES cells make between self-renewal and differentiation into the neuronal lineage, by
utilising 52 human ES cell lines. It will develop internationally agreed standardised protocols and tools for growing
and manipulating ES cell lines, and for monitoring their phenotypic, genetic and epigenetic stability. This knowl-
edge will be disseminated to the wider scientific community to make the best use of the existing stem cell lines, and
ultimately will allow the culture and exploitation of hES cells.It will also address the technology for deriving induced
Pluripotent Stem (iPS) cells and explore whether iPS cells have genetic, epigenetic and developmental properties
equivalent to human ES cells. If this technology can be established, and if the derived cells are indeed identical to
ES cells, then this approach may in the future reduce the need for working with embryo-derived stem cells.
A first step towards regenerative medicine involves finding a means to cause controlled dedifferentiation of
adult tissue. The project PLURIGENES investigates the controlled de-differentiation of adult tissue in order to
discover the function of genes controlling pluripotency and de-differentiation in the central nervous system, so
as to ultimately combat diseases such as brain injury and/or ageing. The project is based on the identification
of candidate pluripotency associated genes evolutionarily conserved between different model organisms. The
knowledge generated on self-renewal pathways (which are often deregulated in cancer stem cells) might also
lead to improved outcomes in the treatment of human tumours.
One of the big challenges for the next decade is to understand the regulatory network of TFs that control cel-
lular functions. EuTRACC determines the regulation of the genome by mapping the regulatory pathways and
networks of TFs (the ‘Regulome’) that control the activity of ES cells and the process of differentiation into neural
tissues and the blood system. The project utilises multidisciplinary approaches by applying genetics, proteomics
and genomics tools in the mouse mainly, which are complemented by functional assays in other model organ-
isms. The neural and hematopoietic tissue types were selected because of their well-characterised differentiation
pathways and their existing clinical applications.
Several of these projects cooperate closely with international efforts. ESTOOLS will play a significant role in the
development of standardised techniques for hES cells not only in Europe, but throughout the world, by working
together with the International Stem Cell initiative (ISCI), which addresses issues of standardisation of markers
and techniques for studying human ES cell lines. %542!## will collaborate with the International Regulome
Consortium (IRC), a worldwide consortium that will map the genetic regulatory nodes and networks that control
the function and lineage determination of embryonic and adult stem cells, with immense implications for devel-
opmental biology, disease and regenerative medicine.
The discovery of the RNA-interference mechanism that can degrade mRNA from a specific gene was reported
in 1998 and led to the 2006 Nobel Prize in Medicine and Physiology. This mechanism is activated by double-
stranded RNA which leads to degradation of the target mRNA so that the corresponding gene is silenced and no
protein is produced. RNA interference occurs in plants, animals, and humans and is already being widely used
in basic science as a method to study the function of genes and it may lead to novel therapies in the future. These
discoveries have revealed a previously unknown role for RNA as a silencer of gene expression, to its previously
understood role as a cellular messenger that directs protein synthesis.
The exciting discoveries in RNA biology and the non-protein coding RNAs as the ‘second genome’ are tackled
by several FP6 CPs (SIROCCO and RIBOREG are examples), including the increasing importance of post-tran-
scriptional regulation of gene expression (an example is EURASNET).
The SIROCCO project studies the role of non-protein coding genes as organisers and coordinators of the organ-
ism’s complexity. It investigates the role of small regulatory RNAs (sRNAs) in health and disease, with particular
emphasis on cancer, neurological diseases and developmental regulation, by using HTP technologies and bio-
informatics. It will determine the tissue and cell-type miRNA expression, optimise methods of sRNAs detection,
characterise the molecular machines responsible for both miRNA and siRNA biogenesis, and dissect sRNA
regulatory networks through the combination of multidisciplinary methods.
The RIBOREG project identifies novel non-coding RNA (ncRNA) genes linked to cell differentiation and disease
and analyse their mechanisms of action by developing a multidisciplinary approach integrating bioinformatics,
cell biology, genetics and genomic strategies. The BACRNAs project will identify non-coding RNAs involved
in bacterial pathogenicity and the identification of targets (virulence factors) controlled by ncRNAs involved in
virulence. RNABIO is an SSA: its main contribution was the organisation of an international workshop on com-
putational approaches to non-coding RNAs, with the main objectives of presenting and discussing the state of
RNA computational biology so as to identify needs and propose new developments.
The human genome contains a surprisingly low number of protein-coding genes — approximately 22 000. However,
the human proteome consists of approximately 100 000 protein isoforms. Part of the answer is alternative messenger
RNA (mRNA) splicing. The EURASNET NoE aims to develop an integrated approach to the study of alternative splic-
ing: it will provide durable structures that will change the way research in this field is carried out in Europe; establish
an ambitious, innovative and multidisciplinary programme of joint research activities with high impact; spread ex-
cellence within Europe; disseminate knowledge about alternative splicing in molecular biology and particularly in
medical communities; and foster public awareness of genomics and RNA research and their applications.
ĺ#HRONOBIOLOGYĺ
The circadian clock is a basic biological process that enables organisms to anticipate daily environmental
changes by adjusting behaviour, physiology and gene regulation. It impacts health and quality of life in
regulating sleep and well-being, in the consequences of shift work, in medical diagnosis and therapy, and in
age-related changes.
The general objective of TEMPO combines functional genomics, proteomics, cell signalling, systems biology and
pharmacokinetics, and will design mouse and in silico models to allow the prediction of optimal chronotherapeu-
tic delivery patterns for anti-cancer drugs.
ĺ"IOLOGYĺOFĺPROKARYOTESĺANDĺOTHERĺORGANISMS
The EC is also supporting multidisciplinary functional genomics research projects in prokaryotic organisms such
as bacteria and other organisms.
The BACELL HEALTH consortium aims to unravel the integrative cell stress-management systems and stress-
resistance processes required to sustain a bacterial cell when exposed to types of environmental signals. There
are also other projects using bacteria to understand the function of basic biological processes (like BaSysBio) and
applying systems approaches to understand transcriptional regulation.
DIATOMICS will make use of whole genome sequences from diatoms to provide information on gene function
and its relationship to ecology and evolution.
ĺ3YSTEMSĺ"IOLOGYĺ
Systems biology, now an emerging discipline, has gained popularity over the past few years. Each cell, organ
or tissue is a dynamic biological system. The cellular functions are controlled by many genes, proteins and sig-
nalling and metabolic processes. Technological and computational advances have enabled the acquisition and
analysis of large datasets obtained by diverse biological systems at multiple levels. Global measurements of
DNA have yielded data on sequence and genotype and information about chromatin structure. RNA measure-
ments have enabled genome-wide transcriptional profiling and information about alternative splicing and non-
coding RNAs. Proteomics approaches using mass spectrometry and more recently protein arrays have permitted
the global identification and quantification of proteins in their biological context. Furthermore, these technologies
have allowed the quantification of post-translational modifications and revealed dynamic protein-protein and
protein-DNA interactions. Great progress has also been made in measuring metabolic fluxes, and emerging
imaging technologies are providing important insights into biological function.
However, despite these advances, the link between complex biological networks and phenotype remains an
enormous challenge.
In order to gain deeper insights and ultimately a quantitative understanding of the complex and dynamic proc-
esses of living organisms (e.g. environmental adaptation, ageing, and immune defence) of the cells, it is neces-
sary to view the systems as a whole.
Systems biology promises to build up an integrated picture of the regulatory processes at all levels, from genome
to proteome, from organelles to cells and tissues, and the understanding of the whole organism, by integrating
functional data into a cohesive model. This stands in contrast to the standard reductionistic approaches of the
twentieth century, with biologists analysing functional information on organisms based on a single gene or a
single protein at a time.
There are two approaches proposed in systems biology. The top-down approach presupposes that it is not neces-
sary to know all the details of the ways in which cells work in order to make useful predictions about how organism
The ultimate goal of biology is to understand biological systems in sufficient detail to enable accurate, quantita-
tive predictions about the behaviours of biological systems, including predictions of the effects of modifications
of the systems such as disease. The hope of the rapid translation of genomic information into novel drugs has
foundered on the reality that disease biology is complex. Systems biology aims ultimately to develop predictive
models of human disease. Currently, integration of ‘-omics’ data within the context of controlled gene expression
or drug perturbations of complex cell and animal models (and in the context of clinical data) is the basis for
systems biology efforts at a number of drug companies.
Such research has a strong multidisciplinary nature and the collaboration between different stakeholders, univer-
sity, research institutes, biotech companies and clinical centres is a prerequisite for success. The subject requires
collaboration between a broad spectrum of scientific disciplines including biology, physics, chemistry, computer
science and engineering. A collaborative approach is a prerequisite to achieving major breakthroughs.
FP6 activities
The EU is emerging as a major world player in the development of systems biology in Europe. An important fund-
ing effort has been initiated in FP6 through the support of collaborative research projects and through a number
of key studies and workshop events that have helped to integrate this emerging community.
In FP6, a number of systems biology projects predominantly initiated in 2005 have already demonstrated that
a systems approach can indeed work, to provide both a deeper understanding of biological processes and pre-
dictive potential for applications. These projects have major links to ongoing worldwide research programmes,
national programmes, and Europe-wide support and links (EMBL, EMBL-EBI).
Within FP6, the EC has already funded several pilot research projects paving the way toward systems biology.
These projects may be grouped into the following general categories:
Some of these projects (COMBIO, COSBICS and DIAMONDS) are already applying systems biology ap-
proaches to model cellular signalling pathways. Other projects (QUASI and AMPKIN) aim for a systematic
quantitative understanding of intracellular and extracellular signalling pathways of disease relevance, with
ultimate goals of building predictive pathway models. All of these projects demonstrate that the develop-
ment of computational biology and integrated bioinformatics databases of diverse ‘-omics’ data is an es-
sential component for the successful implementation of systems biology approaches.
The DIAMONDS project aims to demonstrate the power of a systems biology approach to study the
regulatory network structure of the most fundamental biological process in eukaryotes, the cell cycle, in
different species.
In the AMPKIN project, experimental and theoretical studies will be integrated to achieve an advanced under-
standing of the dynamic operation of the AMP-activated protein kinase signalling pathway. This pathway plays
a central role in monitoring the cellular energy status and controlling energy production and consumption.
EMI-CD, ESBIC-D and BioBridge are using systems biology approaches to gain new insight into highly
complex diseases, such as trisomy related illnesses (Down’s syndrome) and various cancers.
The main purpose of EMI-CD is to provide a software platform complex enough to cope with various ex-
perimental techniques, connecting several modules necessary for the in silico modelling of complex disease
processes such as cancer and diabetes.
VALAPODYN validates predictive dynamic models of complex intracellular pathways related to the cell
death and survival. It develops a new systems biology approach to model the dynamics of molecular inter-
action networks related to neurodegeneration. The ultimate goal is to select and validate drug targets for
human pathologies associated with neurodegeneration.
SysProt develops a new paradigm for the integration of proteomics data into systems biology. It will produce
quantitative proteomics data, and study post-translational protein modifications via the development of compu-
tational analysis, in order to gain understanding on the progression of complex diseases such as diabetes.
BioBridge focuses on the application of simulation techniques for integrated genomic, proteomic, metabo-
lomic and kinetic data analysis, in order to create models for understanding complex diseases at the systemic
level, with an emphasis on heart failure, chronic obstructive pulmonary disease and type II diabetes.
To prepare the best research environment in Europe for systems biology, the EC is already supporting several
SSAs and CAs.
EUSYSBIO laid the foundations for the successful start of European systems biology research,
implementing networking activities and identifying the strengths and weaknesses in European systems
biology. SYMBIONIC is creating a broad European network of research institutions and industries with
interdisciplinary expertise in the systems biology field, which will be a driving force for future ambitious
initiatives in neuronal cell modelling.
ESBIC-D aims at organising a Europe-wide systems approach to combat complex diseases. The project
will network leading groups in the fields of cancer research, genomics, proteomics and computational biol-
ogy to strengthen the expertise and research infrastructure in Europe.
SYSBIOMED explores the potential application of SB to medical research in major disease areas (infec-
tious, neurodegenerative, metabolic and cardiovascular diseases and cancer), and its applications in drug
development. A series of workshops will be organised to promote European collaboration and to contribute
to the breaking down of barriers — between theoreticians, basic researchers and clinicians interested in
medical applications.
YSBN is a CA which focuses on defining standards, methods and concepts of systems biology using the
model organism S. cerevisiae.
IP, NoE
Experimental Tools and Tools for Proteomics, transcriptomics, structural genomics,
CA, STREP technologies for ”omics” population genetics, metabolomics, imaging
FP7 activities
The EU FP7 programme is already playing a major role in this important and rapidly expanding research field
by establishing multidisciplinary networks in Europe that will catalyse progress and excellence in this field. The
FP7 first call for proposals provided an important boost for large-scale European initiatives, by allocating
a total budget of `45 million to the following large scale integrating projects.
SYBILLA, a large scale integrating project, aims to understand at the systems level, how T-cells discriminate
foreign from auto-antigens and will address modelling of T-cell activation. The project will develop technologi-
cal and mathematical tools to generate and integrate high-density quantitative data describing T-cell activation
in health and disease, placing particular emphasis on multiple sclerosis. T-cell activation is a complex process,
relying on multiple layers of tightly controlled intracellular signalling modules, defects in which can cause severe
and chronic disorders such as autoimmune diseases.
The APOSYS project studies the basic cellular mechanisms of apoptosis. This multidisciplinary consortium brings
together and networks experimental biologists, biomathematicians, biostatisticians, computer scientists and clini-
cal scientists to examine cell death pathways in health and disease, with an emphasis on cancer and AIDS. It
complements the systems approach with a series of in silico, in vitro and in vivo model organisms and tissue
UNICELLSYS set as an overall objective the quantitative understanding of fundamental characteristics of eukaryotic
unicellular organism biology, using yeast as model organism. The project goes far beyond the state of the art in terms
of dynamic modelling of cellular subnetworks controlling complex biological processes such as control of cell growth
and proliferation. It is expected to deliver new knowledge on important biological processes relevant to human health
(cell growth and proliferation) but will also generate economic value in the form of new computational tools and ap-
proaches for systems biology that will be of general applicability to other systems in more complex organisms.
EuroSyStem is a large European effort that brings together elite European research teams to create a world-
leading programme in fundamental stem cell biology, with the main focus on the paradigmatic mammalian stem
cells: haematopoietic, epithelial, neural and embryonic. Cutting-edge multidisciplinary technologies such as
cytometry, transcriptomics, RNA interference, proteomics and single cell imaging, will be used to generate new
knowledge on stem cells differentiation in terms of cellular hierarchy, signalling, epigenetics, de-regulation, and
plasticity. An important bioinformatics and computational platform will be established to mine information and
subsequently to model these complex differentiation pathways.
From biological pathways in unicellular eukaryotic organisms to human cells and organs, there is a need to
combine, integrate and extend existing data sources and screen different heterogeneous data resources. These
large-scale projects on systems biology are expected to integrate dispersed capabilities and assemble the critical
mass necessary to enable systems approaches, as well as to secure European excellence and competitiveness
and the exploration of new directions for the field. The quantitative data delivered should serve as the basis from
which to design robust models with predictive value. They should produce new knowledge on basic biological
processes relevant to health and diseases.
Project Acronym 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 FP
EYSYSBIO SSA E0.5m FP6
SYMBIONIC SSA E0.2m
EMI-CD STREP E1.9m
QUASI STREP E1.9m
COMBIO STREP E2m
COSBICS STREP E1.7m
DIAMONDS STREP E2.5m
EU-US Workshop SSA E0.06m
ELife SSA E0.48m
ESBIC-D STREP E1.9m
YSBN CA E1.3m
AMPKIN STREP E2.1m
RIBOSYS STREP E2.4m
EUROBIOFUND SSA E0.9m
VALAPODYN SME-STREP E1.5m
AGRON-OMICS IP E12m
BaSysBio IP E12m
BioBridge SME-STREP E1.8m
SYSBIOMED SSA E0.36m
SysProt SME-STREP E2.1m
Streptromics SME-STREP E2.9m
SYSCO SME-STREP E1.8m
Proust SSA E1.5m
APOSYS IP E11.1m FP7
SYBILLA IP E11.1m
UNICELLSYS IP E11.03m
EuroSysStem IP E11.03m
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 FP
Fig. 15: Runtime of current EU-funded collaborative research projects in systems biology
(funding period started in 2004 for FP6 projects-most projects extend well beyond 2007; funding period started in 2008 for the FP7 first call projects)
For an emerging and booming field like systems biology, it is rather difficult to identify which are the timely ideas
to investigate using an EU large-scale coordinated approach. The large-scale CPs will create the critical mass
of multidisciplinary expertise that is necessary for enabling complex systems approaches. Therefore, the EC via
its Genomics and Systems Biology programme published the FP7 third call for proposals in September 2008,
implementing a bottom-up approach via a two-stage selection procedure for the first time in the Health priority.
The scientific community is invited to submit proposals for large integrating projects on the following topic:
In summary, to face the challenges of the systems biology era, the EC’s FPs for RTD have al-
ready provided, between 2003 and 2008, more than `150 million for collaborative research
projects. With such substantial funding, the EU is emerging as a major world player in the development of
systems biology in Europe and will continue to do so in the future.
SB: organisms
SB: tissues/organs
SB: pathways
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
FP6
FP7
Annex I
Funding instruments and schemes in FP6 and FP7
Compared to FP5 (1998–2002), which mainly supported small and medium collaborative research projects, FP6
(2002–2006) has additionally offered more ambitious ‘new funding instruments’, namely IPs and networks of ex-
cellence (NoE). These two project types are more ambitious in size and scope than the research projects funded
previously by the EU. Both types of projects aim to stimulate and sustain world-class research in a specific area of
fundamental genomics and to improve the organisational aspects of European research in the specified topic. How-
ever, IPs and NoE have a different centre of gravity. With an IP the balance is towards achieving ambitious, clearly
defined scientific objectives; with a NoE the balance is shifted towards tackling the fragmentation of European
research in a specific field, so as to provide an improved organisational structure in which research can flourish.
It is clear that the ‘new instruments’ of FP6 have enabled European scientists to achieve a major critical mass in
very competitive areas of functional genomics and have really given European research a global profile.
&UNDINGĺINSTRUMENTSĺINĺ&0
IPs are large-scale projects aiming to support world-class objective-driven research, where the primary deliver-
able is generating new knowledge. In addition, by mobilising a critical mass of resources, IPs should also have
a structuring effect on European research (see Figure 17 for the graphical representation on the goals of an IP).
The activities integrated by an IP may cover the full research spectrum from basic to applied research, and
should contain:
■ objective-driven research;
An IP should bring together a critical mass of research excellence and resources to achieve its ambitious objec-
tives. The European Community funding for an IP in the fundamental genomics programme ranges from `8 to
`13 million, their duration from 36 to 60 months, with an average of `11.2 million per project and 48 months
duration for the majority of the projects.
Increasing EU competitiveness
Fig. 17: Graphical representation of the structure and the goals of an Integrated Project in FP6 (2002-2006)
NoE are large-scale projects with the goal of overcoming fragmentation in the European research landscape
and strengthening European excellence in a given area (see Figure 18 for a graphical representation of the
goals of a NoE). Their purpose is to reach a durable restructuring/shaping and integration of efforts and
institutions or parts of institutions (labs, departments, units, teams, etc.) in areas where this is necessary. The
success of a NoE is not measured only in terms of scientific results, but also by the extent to which the fabric for
researchers and research institutions in a given field has changed due to the project, and the extent to which
the existing capacities have become more competitive as a result of this change.
A NoE is implemented through a Joint Programme of Activities, which encompasses the following:
■ Integrating activities: These aim at structuring and shaping the way participants carry out research in
the topic (e.g. coordinated programming, sharing research facilities, tools and platforms, joint management
of the knowledge portfolio, schemes for increasing staff training and mobility, staff exchanges, shared
information and communication systems).
■ Jointly executed research: A world-class research programme is an obligatory part of the Joint
Programme of Activities or JPA (for example, to generate new knowledge in the research topic and to develop
new research tools and platforms for common use).
■ Activities for spreading excellence: An essential mission of a NoE is to spread excellence beyond
its boundaries. Typical examples of such activities would be the following: joint programmes for training
researchers and other key staff to ensure the sustainability of Europe’s excellence in the topic, communication
campaigns for disseminating results (and raising public awareness of science), and networking activities to
encourage knowledge transfer and innovation.
NoE should pursue ambitious goals and gather the critical mass needed to ensure their achievement. The Euro-
pean Community grant to a NoE in the fundamental genomics areas ranges from `10 to `12.5 million, their
duration from 48 to 60 months, with an average of `10.7 million per project and 60 months duration for the
majority of the projects.
Fig.18: Graphical representation of the goals and the structure of a network of excellence in FP6 (2002-2006)
STREPs are multi-partner research projects, with the goal to support research, technological development and
demonstration or innovation activities of a more limited scope and ambition than IPs. They are an evolved form of
the shared-cost RTD projects and demonstration projects used in FP5, and their main deliverables are to produce
new knowledge and improved tools and technologies in fundamental genomics.
The European Community financial support for a STREP in fundamental genomics ranges from `1.5 to `2.5 mil-
lion, their duration from 36 to 48 months, with an average of `2.1 million per project and 36 months duration
for the majority of the projects.
STREPs were also funded during the fourth call of FP6 with the specific goal of supporting projects for develop-
ing and/or improving tools and technologies development, and of encouraging SMEs’ research and innova-
tion efforts. The goal was that 30% of the EC contribution to be allocated to the SMEs. These projects are
entitled SME-STREPs in the current publication.
CAs do not support research and development activities per se; they promote and support the networking and
coordination of research and innovation activities aiming at improved integration of European research. CAs are
a continuation of the concerted actions/thematic networks used in FP5, in a reinforced form.
The European Community financial contribution for a CA in fundamental genomics ranges from `0.5 to `1.3
million, their duration from 24 to 48 months, with an average of `0.8 million and 36 months respectively.
SSAs are more limited in scope than the accompanying measures of the previous FPs. They aim to:
■ promote and facilitate the dissemination, transfer, exploitation, assessment and/or broad take-up of
past and present programme results (over and above the standard diffusion and exploitation activities of
individual projects);
■ contribute to strategic objectives, notably regarding the ERA (e.g. pilot initiatives on benchmarking,
mapping, networking, etc.);
■ prepare future community RTD activities, (e.g. via prospective studies, exploratory measures, pilot ac-
tions, etc.).
The European Community funding contribution for an SSA in fundamental genomics ranges from `0.06 to `0.5
million, their duration from 12 to 36 months, with an average of `0.3 million and 24 months respectively.
&UNDINGĺSCHEMESĺINĺ&0ĺ
FP7 projects are all categorized with the general term collaborative projects.
The large integrating projects could be considered an evolution of the IPs in FP6.
These projects will support objective-driven research projects aiming at developing new knowledge, new
technologies, products, demonstration activities or common resources for research, to improve European
competitiveness or to address major societal needs.
They include the following activities:
■ project management;
The European Community funding contribution for CP-IPs in the Health theme should be more than `6 million
and maximum of `12 million. In the Genomics and Systems Biology programme during the implementation
of the FP7 first call for proposals, the funding ranges from `11 to `12 million, their duration from 48 to 60
months, with an average of `11.7 million and 48 months respectively.
These projects could be considered as a continuation of FP6 STREP projects and are research projects with
lower ambitions than IPs.
The European Community funding contribution for CP-FRPs in the Health theme should be `3 million to less
than `6 million. In the Genomics and Systems Biology programme during the implementation of the FP7
second call for proposals (with a September 2007 deadline), currently under negotiation, the funding ranges
from `2.5 to `2.99 million, their duration from 36 to 48 months, with an average of `2.7 million per project
and 36 months duration for the majority of the projects.
These projects refer to Coordination and Support Actions (CSAs) and do not support research per se but
rather coordination activities with objectives similar to those of FP6.
The European Community funding contribution for CP-CSAs in the Health theme is generally in the range
of up to `1.5 million, although there is no upper limit. In the Genomics and Systems Biology programme
during the implementation of the FP7 second call for proposals (projects currently under negotiation), the
EC funding ranges from `0.5 to `2.7 million, and the duration from 24 to 36 months.
At the beginning of FP6, a global expression of interest was established for the first time in the FP, and the most
innovative ideas for European collaborative research were selected. This concept has been applied in the whole
thematic area of Life Sciences, Genomics and Biotechnology for Health. In this section, we will concentrate on
the Fundamental Genomics activity area. The European scientific community has submitted 550 expressions of
interest, and these have been evaluated by eminent scientists both within and outside Europe. This high-level
evaluation process led to the strategic areas of research that defined the specific topic for calls for proposals,
mostly for the large-scale projects in the FP6 first, second and third call topics.
The rest of the calls have been developed by consulting the scientific community via EC’s strategic workshops
(see Annex III). The Scientific Advisory group was set up by the EC to provide input on the strategy and the imple-
mentation of the work programme in the Life Sciences theme in FP6: this group’s valuable advice is an important
source of consultation on the work programmes (for more information, please see http://cordis.europa.eu/fp6/
eags.htm and http://ec.europa.eu/research/fp7/index_en.cfm?pg=eag).
The EC also acknowledges the important role of the Member States’ recommendations in the final implementation
of the work programme.
During FP6, the EC organised a number of successful workshops in collaboration with the scientific community,
to identify the challenges and the future developments in different areas of fundamental genomics, along with
new initiatives that have contributed to strategies in FP7. The following workshops were organised by the Unit of
Fundamental Genomics — this name was updated to the Genomics and Systems Biology Unit in FP7 (for further
information, see http://cordis.europa.eu/lifescihealth/genomics/home.htm).
■ Bioinformatics Structures for the Future, in March 2003, with the goal of setting a research agen-
da in the field for structuring European bioinformatics research;
■ Workshop on Mouse Genetics, in July 2003, with the aim of setting priorities for mouse functional
genomics research in Europe;
■ Computation Systems Biology: its Future in Europe, in September 2003, with the aim of defining
a research and policy agenda to promote the field of computational systems biology (CSB) in Europe;
■ Meeting on population genetics in Europe, in September 2003, in order to identify priorities for
research in population genetics and related areas;
■ Workshop on Structural Genomics, in October 2003, with the aim of identifying the strengths,
weaknesses and future opportunities for structural genomics in Europe;
■ Conference on European Structural Genomics & Proteomics Research combined with the
joint meeting of EU-funded projects, in October 2004, with the aim of creating synergies between the
projects by clustering and networking, of disseminating best practices and success stories to establish
gateways between disciplines; of debating and formulating a proposal on the current and future policies
needed for SG in Europe;
■ Functional Genomics Research: Future Perspectives in October 2004, with the aim of identifying
the future challenges and developments of the functional genomics field for future research policies actions,
in view of establishing genomics research for FP7;
■ Workshop on Systems Biology in December 2004, where European scientists identified key areas in
systems biology for development in the near future;
■ Conference on Funding Basic Research in Life Sciences: Exploring opportunities for Eu-
ropean synergies in December 2004, a joint effort of Directorate F (Life Science, Genomics And
Biotechnology for Health in FP6 & Directorate E (Food Quality And Safety);
■ Human genetic variation workshop in March 2006, exploring the need for a grid-linked set of
databases in this area;
■ Mouse functional genomics workshop in March 2007, concluding with recommendations for
international collaboration in the field of mouse as a model for human disease;
■ EU-US workshop on ‘How Systems Biology Could Advance Cancer Research’ in May 2008,
drawing up suggestions for international collaboration on systems biology of cancer.
For more information, including the published reports for some of the workshops, see http://cordis.europa.eu/
lifescihealth/genomics/home.htm. Information can also be found on the FP7 Health website, at http://cordis.
europa.eu/fp7/health/home_en.html.
The present section provides a short overview of the evaluation procedure in the thematic priority of Life Sciences,
and more specifically focuses in the area of Fundamental Genomics.
The procedure for evaluation of proposals is based entirely on the ‘Guidelines on proposal evaluation and project
selection procedures’, which can be found at: http://fp6.cordis.lu/lifescihealth/call_details.cfm?CALL_ID=148,
and which serves as the basis for the following brief presentation.
The EC appoints independent experts to assist in the evaluation of proposals. In general, independent experts
are expected to have skills and knowledge appropriate to the areas of activities in which they are asked to as-
sist. Details of potential independent experts are maintained in a central database. This database may be made
available, on request, to national authorities in the Member States and countries associated to the FPs. The names
of the independent experts assigned to individual proposals are not made public; however, at regular intervals,
the EC publishes the list of independent experts used per activity/research area, on the Internet.
The EC takes all reasonable steps to ensure that each expert is not faced with a conflict of interest in relation to
the proposals on which he/she is required to give an opinion. To this end, the EC requires experts to sign a dec-
laration that no such conflict of interest exists at the time of their appointment and that they undertake to inform
the EC if one should arise in the course of their duties. When so informed, the EC takes all necessary actions to
remove the conflict of interest. The experts are obliged to maintain the confidentiality of the information contained
within the proposals they evaluate and of the evaluation process and its outcomes and to act with strict impartial-
ity. A conflict of interest and confidentiality declaration will be signed by independent experts.
The overall evaluation and project selection process is summarised in the following diagram.
All independent experts are briefed in writing and orally before the evaluation by representatives of the EC’s
service in charge of the call, in order to inform them of the general evaluation guidelines and the objectives
of the research area under consideration.
The proposals are sent to the expert evaluators at their normal place of work. Each proposal is evaluated
against the applicable criteria relevant to each funding instrument independently by several experts who fill
in individual evaluation forms giving marks in each criterion and providing justification of marking. These
comments serve as input to the consensus discussion and related consensus report that takes place in Brussels.
The number of evaluators legally required is five for IPs/NoE and three for the other instruments. The EC has
established as a general practice the evaluation by a number of seven to nine evaluators for IPs/NoEs and
five for the other instruments, in order to further strengthen the quality of the evaluation procedure.
Written opinions from external reviewers are applied specifically for the large projects (IPs, NoE), where most
of the top European specialists in the field are involved in a given proposal. Therefore, to obtain an independ-
ent high-quality assessment, several specialists in the field, mainly from outside Europe, are invited to review
Proposal
Eligibility
Individual Evaluation
Consensus
Ethical Issues
Thresholds
(OPTIONAL) Hearings
Panel
Ranking by EC
Negotiation Result
Consultation of Programme
Committee if required
EC Funding Decision
and/or Rejection Decision
each proposal. The external reviewers are asked to provide their written opinion of the scientific quality of the
proposal. These written opinions are provided to the expert evaluators prior to the meeting of the consensus
group in Brussels, but after the expert evaluators have completed and forwarded to the EC services their in-
dividual assessment reports on the proposals assigned to them. Consideration of the written opinions of the
external reviewers makes up an important aspect of the consensus group’s discussions in Brussels.
Different consensus groups operate in parallel in different groups of closely related topics. The propos-
als passing the thresholds are reviewed by a final panel composed of several experts from each of the
several consensus groups. The final panel produces a ranking list of proposals in order to advise the EC
on which projects to select for funding.
Separate parallel consensus panels are convened in Brussels. The goal is that for each proposal all the
experts reach an agreement on a consensus mark for each of the blocks of evaluation criteria based on
the comprehensive discussion. They justify their marks with comments suitable for feedback to the pro-
posal coordinator. The discussion of the proposal continues until a consensus is achieved, i.e. a conclu-
sion with which all agree regarding the marks for each criterion and the accompanying comments. In the
event of persistent disagreement, the EC official supervising the evaluation of that proposal may bring in
up to three additional evaluators to examine the proposal.
Immediately after completion of the consensus panels, an integrated final panel discussion is convened in Brus-
sels to examine and compare the consensus reports and marks of the independent consensus panels, to review
the proposals with respect to each other and, in specific cases (e.g. equal scores) to make recommendations on
a priority order of proposals. A panel rapporteur (who may also be the panel chairperson) is appointed to draft
the panel’s advice. An EC official may act as moderator of the panel. The role of the EC moderator is to ensure
fair and equal treatment of the proposals in the panel discussions. The outcome of the panel meeting is the panel
report recording the deliberations of the panel containing the following: an evaluation summary report (ESR) for
each proposal and a ranked list of proposals passing thresholds, along with a final mark and the panel recom-
mendations for priority order.
At this stage, the EC services review the results of the evaluation by independent experts, make their assessment
of the proposals based on the advice from these experts and prepare the final evaluation results.
The EC services draw up a final ranked list of all the proposals evaluated and of those passed the required thresh-
olds. Due account is taken of the marks received and of any advice from the independent experts concerning the
priority order for proposals. The list of proposals to be retained for negotiation takes into account the budget avail-
able. Negotiation may cover any scientific, legal or financial aspects of the proposal, based on the comments of the
independent experts and on any other issue that was taken into consideration at the ranking stage. If negotiations
are successful, the EC may then enter into the contract with the coordinator and the other contractors.
The procedure for evaluation of proposals is based entirely on the ‘Rules for submission and the related evalua-
tion, selection and award procedures’, which can be found at ftp://ftp.cordis.europa.eu/pub/fp7/docs/calls/
fp7-evrules_en_pdf.zip.
The basic structure of the procedure is similar to the one described in FP6, with some minor adaptations.
The evaluation criteria in FP7 have been consolidated to avoid repetition and the high level of complexity expe-
rienced during the FP6 evaluations.
The evaluation criteria applied for each funding instrument in FP6 are described below.
Each of the criteria may differ depending on the type of the funding instrument (described in Annex I). The evalu-
ation criteria are ranked as follows:
0: the proposal fails to address the issue under examination or cannot be judged against
the criterion due to missing or incomplete information;
1: poor;
2: fair;
3: good;
4: very good;
5: excellent.
The total score for a NoE could be a maximum of 25 with threshold 20.
The total score for STREP could be a maximum of 30 with threshold 21.
The total score for an SSA could be a maximum of 25 with threshold 17.5.
■ Scientific and/or technological excellence (relevant to the topics addressed by the call) (threshold score: 3).
Under this criterion, the following aspects will be evaluated: soundness of concept and quality of objec-
tives; progress beyond the state of the art; and quality and effectiveness of the S/T methodology and
associated work plan. The relevance of a proposal is considered in relation to the topic(s) of the work
programme open in a given call, and to the objectives of a call. When a proposal is partially relevant
Table 2: Quality of funded projects in the Fundamental Genomics area: an overview of the average total scores of the funded projects
#! p p
#0 )0 p
p
* The total score is divided by the number of the criteria per funding instrument, in order to have a normalised score
comparison between different types of projects.
** The number of criteria has been reduced to 3 in FP7, and hence the maximum score is 15.
■ Quality and efficiency of the implementation and the management (threshold score: 3). under this criterion
the following aspects will be evaluated: appropriateness of the management structure and procedures;
quality and relevant experience of the individual participants; quality of the consortium as a whole (includ-
ing complementarity and balance); and appropriateness of the allocation and justification of the resources
to be committed (budget, staff, equipment).
■ Potential impact through the development, dissemination and use of project results (threshold score: 3). Under
this criterion, the following aspects will be evaluated: contribution, at European and/or international level, to
the expected impacts listed in the work programme under relevant topic/activity; appropriateness of measures
for the dissemination and/or exploitation of project results, and management of intellectual property.
Impact is considered in relation to the expected impact listed in the work programme. The total score for a CP
could be a maximum of 15 with threshold 10.
Table 3: Number of proposals evaluated, proposals funded and success rates in all the calls for proposals in FP6
in the Fundamental Genomics activity area, including the first call of FP7
3ECONDĺCALLĺAPPLICATIONSĺ
DEADLINEĺ
4HIRDĺCALLĺAPPLICATIONSĺ
DEADLINEĺ
&OURTHĺCALLĺAPPLICATIONSĺ
DEADLINEĺ
&IRSTĺCALLĺAPPLICATIONSĺ
DEADLINEĺ
* Four calls for proposals with an overall budget of `594 million were open in the Fundamental Genomics programme
in FP6 during 2002 and 2005. Some 441 proposals were evaluated and 127 projects were selected for funding, with
an overall average success rate of 29%.
** The average success rate represents the success rate for all types of funding instruments. If we would calculate the
success rate, separately for IPs/NoEs, STREPs/CAs and SSAs, which had different budget allocations, one would
note a variation on the success rate. The average percentage per call is calculated by dividing the total number of
proposals funded in all funding instruments by the total number of proposals evaluated.
*** In FP7, the success rate generally concerns the large IPs for the first call. On the whole, the average success rate for the
Health theme ranges from 15% to 17% and could vary considerably in some areas, in relation to the higher number
of applications received.
Table 4: Number of funded proposals per funding instrument and total budget allocated per funding instrument
Total EC Percentage
Funding Number of financial budget spent/
instrument funded projects contribution type of funding
(million `) instrument
)0
.O%
342%0ĺINCLUDINGĺ
3-%
342%0
#!
Average EC Average
Average duration
Funding contribution* number of
(months)/
instrument (million `/ partners**/
instrument
instrument) instrument
ĺMAJORITYĺĺWITHĺONEĺ
.O% ĺp
LASTINGĺ
342%0ĺINCLUDINGĺ
ĺp ĺp ĺMAJORITYĺ
3-%
342%0
* The budget is indicative and is calculated based on the maximum EC contribution at the start of the project; it does not
relate to the final spent by the project for projects not finalised.
** A partner is an independent legal entity, which might include several independent scientific groups belonging to the same
legal entity; partners (independent legal entities) are calculated based on information including amendments of the FP6
projects until the end of 2007.
Percentage EC
Activity type of Number partners/
contribution/activity
partners* activity type of partners
type of partners
(%
/4(
3-%
* HES: higher education; RES: research institutes; IND: industry; OTH: other (for example, international organisations).
The number of partners has been calculated based on information which includes amendments of the FP6 projects until
the end of 2007. Figures do not include calculation of inclusion or termination of partners — with these included,
numbers may vary.
** The total EC contribution allocated to SMEs in the fundamental genomics area constitutes approximately 7% of the total
EC contribution during FP6 (2002–2006), with an allocated budget of more than `40 million; SME participation
constitutes 84% of the number of industrial activity partners.
Percentage EC
Number of partners/
Countries contribution/country
country group
group
EU-25*
Candidate countries**
4OTAL
* During FP6, the EU comprised 25 Member States; Bulgaria and Romania became Member States in 2007.
The new Member States (from May 2004) are the Czech Republic, Estonia, Cyprus, Latvia, Lithuania, Hungary, Malta,
Poland, Slovenia, Slovakia.
The associated countries are Switzerland, Israel, Iceland, Norway, and Lichtenstein
** Candidate countries for accession in EU during FP6 were Bulgaria, Romania, Croatia and Turkey; Bulgaria and Roma-
nia were candidate countries and are therefore included in this group in the FP6 statistics for the Fundamental Genomics
programme.
*** Third countries. The FP6 programme was open for participation to the International Cooperation target group countries,
which may be found in the relevant FP6 work programmes Annexes. Other third countries, for example industrialised
countries like the US, Canada, Australia and Japan may participate on a case-to-case basis if during the evaluation their
participation is considered essential for implementing the objectives of the respective project; generally speaking, in FP6 the
industrialised countries did not receive EC contributions.
Scientific/Technological Objectives:
A series of interrelated research problems are being dealt with in collaboration between
partners in academia and in biotechnology companies. The partners provide the comple-
mentary expertise required to establish an individualised genome analysis technology by
achieving the following objectives:
s DEVELOP EVOLVE AND APPLY METHODS FOR $.! ANALYSIS FOR SEQUENCING GENOTYPING
and haplotyping, and the elucidation of duplications
s ESTABLISH METHODS FOR HIGH
SENSITIVITY HIGH
THROUGHPUT AND LOW
COST GENE EXPRESSION
profiling
s ESTABLISH TECHNOLOGIES FOR HIGHLY SPECIlC PROTEIN ANALYSIS IN A MANNER THAT CAN BE
read out on microarrays
s DEVELOP A FAMILY OF TECHNIQUES THAT WILL ENABLE ULTRA
SENSITIVE ANALYSES OF PROTEINS AND
nucleic acids in the complexity of biological samples
s ENABLE PARALLEL ANALYSES OF THE FUNCTIONAL CONSEQUENCES OF A VARIETY OF MOLECULAR
alterations in cells by establishing technologies for cell array studies.
Expected Results:
The ambitious plan for the MolTools project is to have developed, by 2007, a next-gen-
eration toolbox for large-scale molecular analyses on arrays and in cells, with the ability
to detect even single molecules. The tools will increase throughput and decrease costs for
analyses of genomes, transcriptomes, proteomes and functional cells. Important progress
towards these goals has been made during the course of the project.
Regarding the development of techniques for single-molecule detection and for the analy-
sis of single cells, Uppsala and Aarhus Universities, in a joint project, have developed
a method for in situ genotyping, visualising single nucleotide allelic variations in single
molecules, directly in cells and tissues, using a combination of padlock probes and rolling
circle replication. An article was published in Nature Methods on how the technology was
applied to genotyping mitochondria in individual cells. Since then, the technology has been
further refined and now permits analysis of nuclear single-copy genes in fixed cell prepara-
tions. The Uppsala lab has published a paper describing a related technology that allows
individual and interacting pairs of protein molecules to be detected in cells.
Potential Impact:
The MolTools project brings together some of Europe’s leading groups developing technolo-
gies for molecular medicine to overcome fragmentation, create synergy and speed up the
development process. The high-throughput, high-precision technologies established in this
programme are expected to be of decisive importance in many forms of molecular biologi-
cal research, and the programme can therefore provide leverage in academic research,
increasing competitiveness in the European Research Area in a global context. The project
also addresses one of Europe’s main challenges in biotechnology: translating technological
innovations into commercially successful products, thereby increasing competitiveness of
the European biotech industry.
Partners
Project Coordinator: Dr. Michael Taussig
Prof. Ulf Landegren The Babraham Institute
Uppsala University Technology Research Group
Department of Genetics and Pathology Cambridge, UK
Dag Hammarskjoldsvag 20
P. O. Box 256 Prof. Arvydas Janulaitis
75185 Uppsala, Sweden Fermentas UAB
ulf.landegren@genpat.uu.se Vilnius, Lithuania
Scientific/Technological Objectives:
We aim to develop novel genomics tools and methods for the determination of transcription
factor binding specificity. These tools will be used for the identification of regulatory SNPs
that predispose to colorectal cancer, and for characterisation of downstream target genes
that are common to multiple oncogenic TFs.
The specific aims are:
1. to develop novel high-throughput multiwell-plate and DNA chip-based methods for
determination of TF binding specificity
2. to determine experimentally the binding specificities of known cancer-associated TFs
3. to predict computationally, and to verify experimentally, elements that are regulated
by these TFs in genes that are essential for cell proliferation
4. to develop an SNP genotyping chip composed of SNPs that affect the function of TF-
binding sites conserved in mammalian species
5. to use this chip for the genotyping of patients with hereditary cancer predisposition,
as well as controls in three European populations, for identification of regulatory
SNPs associated with cancer.
Expected results
This project aims to understand the basic principles involved in growth regulation by on-
cogenic TFs, and is expected to have a major impact on understanding cancer. Identifi-
cation of SNPs associated with low penetrance cancer predisposition would be a major
breakthrough in the effort to understand inheritance of quantitative trait loci, and will have
implications on healthcare at the population level.
The methods developed within the project¹ have already allowed genome-scale prediction
of regulatory elements in the human genome, and the methods developed should make
feasible the analysis of DNA-binding specificities of all TFs, and consequently significantly
improve our understanding of the regulation of gene expression.
¹ Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E and Taipale J: Genome-wide Prediction of Mammalian
Enhancers Based on Analysis of Transcription Factor Binding Affinity. Cell. 124:47-59, 2006.
Potential impact
We expect that the project will lead to the identification of genes that associate with color-
ectal cancer. This will have direct implications on diagnosis and treatment of a cancer type
that affects more than 200 000 Europeans each year.
Methods, tools and instrumentation for advanced genomics developed within the proposed
project will improve EU scientific competitiveness in the rapidly developing field of regula-
tory genomics, and will allow EU scientists to be in a very good starting position to decipher
the genetic code controlling regulation of gene expression.
Keywords:
genomics, molecular genetics, cancer, transcription factors
Partners
Project Coordinator:
Prof. Jussi Taipale
University of Helsinki
Faculty of Medicine
Genome-Scale Biology Research Programme
Yliopistonkatu 4
00014 Helsinki, Finland
jussi.taipale@helsinki.fi
The consortium’s principal technological objective is to generate a platform for the secretion
of a wide range of heterologous proteins, in particular those of therapeutic value, based on
the Tat machinery. Its principal scientific objective is to obtain a clear picture of the ‘global’
role of Tat in a range of pathogenic and non-pathogenic organisms, and to obtain detailed
information on the Tat structure that will lay the foundations for the future design of specific
inhibitors. It is already clear that the Tat system is vital to the pathogenesis of a range of
bacteria. Some bacteria export major virulence factors by this pathway, and disruption of the
Tat pathway impairs the viability of others. Because Tat sub-units are also unique in structural
terms, and completely absent from mammals, the Tat machine represents a superb target for
novel anti-infectives.
Expected Results:
The consortium aims to produce the following results: (1) A detailed structure of Tat complexes
from representative Gram-negative and Gram-positive species. This is an ambitious target.
The project is geared to the efficient delivery of a wide range of Tat complexes, to partners
with track records in the elucidation of membrane protein structures; (2) Development of super-
secreting strains of B. subtilis and S. coelicolor that are capable of exporting heterologous
proteins with high efficiency. These strains will fill major gaps in the present repertoire of bac-
terial vehicles for protein production; (3) Understanding of the overall role of Tat in a limited
series of pathogenic bacteria, including identification of specific virulence determinants that
employ this export pathway; (4) In-depth understanding of the Tat translocation mechanism.
This will be achieved through a combined biochemical/genetic analysis of the Tat transloca-
tion process, and the results will benefit all the elements of this project, mentioned above.
Potential Impact:
The expected deliverables of the Tat machine project include knowledge of a fundamental
biological system, the Tat nanomachine, which is of vital relevance to human health. The
This project represents a large-scale pluri-disciplinary effort to decipher the grammar of chor-
date regulatory sequences, and will have a strong impact by building tools and resources that
will enable devising more sophisticated hypothesis regarding regulatory networks, especially
those of TFs which are involved in fundamental biological processes.
Expected Results:
The project has completed its first year and has successfully completed the in silico analysis
of selected transcription factor gene families, as well as the development of a central reposi-
tory for both in silico and in vivo data that is being collected. The repository is available at
the website (http://transcode.tigem.it/). It collates the in silico analyses so far performed,
which indicate the sequence elements predicted to have functional potential based on pub-
lished algorithms, as well as algorithms developed by project members. Some elements
have undergone testing and for those tested in vivo results are also integrated, indicating
those which have acted as enhancers or repressors and those which have yielded no results.
Potential
Impact:
Throughout our project we are contributing widely to the creation, refinement and good use
of standards. We are using open source software and XML data transfers, and generating
novel tools and experimental protocols that will set new standards in both dry and wet
areas of biology, which will help others to explore further the language of gene regulation.
The identification of regulatory modules that are responsible for well-defined expression
patterns will be very useful in gene therapy, thus having a direct impact on health issues.
Finally we are reinforcing European competitiveness by carrying out a transnational and
co-operative project of international visibility via a tight collaboration of partners across
four European countries.
Partners
Project Coordinator:
Dr. Sandro Banfi
Fondazione Telethon
Telethon Institute of Genetics and Medicine
Molecular Biology Unit
Via G. Saliceto, 50
00161 Rome, Italy
banfi@tigem.it
Scientific/Technological Objectives:
The EMERALD consortium aims to establish and disseminate quality metrics (QC), micro-
array standards and best laboratory practices (QA) throughout the European microarray
community, in order to improve the quality of microarray data.
Its specific objectives are as follows:
1. To investigate existing microarray data resources in ArrayExpress, preparing
a full inventory of these and deriving fair and meaningful QC from them;
2. To develop a normalisation and transformation ontology for the description of
data pre-processing information;
3. To bring together all major players in the European microarray community;
4. To structure communication and information exchange within this community;
5. To obtain microarray community agreement on QA;
6. To assess microarray standards for QC. An analysis of QC relevant to vari-
ous data production protocols and available hybridisation standards (spikes,
reference RNAs) will in turn facilitate the development of QA for high data
quality;
7. Key microarray laboratory volunteers to validate QA/QC;
8. To validate the benefits of QA/QC in data compendium modelling;
9. To disseminate microarray standards and best practices to the microarray
community, through a user community website and information exchange and
support networks, and to provide training in their proper implementation;
10. To extrapolate and apply these standards to developing technologies.
Intensity representation on an
Affymetrix array (spatial plot).
The false colours represent the Expected Results:
spatial intensity distribution
of the array. The colour scale The main result of EMERALD will be a quality metrics system for microarray data, accompanied
by ontologies for documentation of microarray meta-data. The project will also generate hy-
was chosen proportional to the
bridisation standards and, in general, integrate European efforts towards laboratory standard-
intensity ranks. This graphical
isation in this area. Recent scientific publications have shown that microarray data produced
representation highlights
under a series of standardisation constraints show improved significance and sensitivity.
problems that result from EMERALD will bring together the main research and innovation operators involved in the devel-
the experimentation such as opment of microarray standards and quality metrics, with stakeholders in the data production
fingerprints, artifactual intensity process (core facilities, companies, technology innovators), data mining (computational and
gradient or dye specific failures systems biology research teams) and data information (toxicology, clinical diagnostics, prog-
for instance. nostics, etc). The coordination and amalgamation of the activities and interests of these diverse
stakeholders will strengthen the European microarray community, consolidating an essential
component of data-driven systems biology.
Partners
Project Coordinator: Dr. Laszlo Puskas
Prof. Martin Kuiper Biological Research Centre of
Ghent University/Flanders Interuniversity Institute the Hungarian Academy of Sciences
for Biotechnology Laboratory for Functional Genomics
Department of Plant Systems Biology Szeged, Hungary
Computational Biology group
Ghent, Belgium Prof. Ulf Landegren
martin.kuiper@psb.ugent.be Uppsala University
Department of Genetics and Pathology
Prof. Arne Sandvik Rudbeck Laboratory
Norwegian University of Science and Technology Uppsala, Sweden.
Norwegian Microarray Consortium
Trondheim, Norway
Scientific/Technological Objectives:
The overall objective of the AUTOSCREEN project is the establishment of an innovative and
automated screening instrument for high-throughput and high-content screens. This instru-
ment will allow standardised, robust, automated and ultrasensitive high-resolution analysis
of RNAs and proteins at cellular and subcellular resolution.
The main goal of the project is to develop an innovative screening platform suitable for high-
throughput and high-content cell-based assays and to demonstrate its suitability for high-res-
olution in situ techniques. This instrument, named AUTOSCREEN, will not only provide the
basis for intelligent and efficient high-content screens, but will also be designed for low cost
genetic, medical, chemical and pharmaceutical screens. It will constitute a significant com-
petitive advantage for the European pharmaceutical and agro biotechnological industry.
Expected Results:
The main expected result of the project is the generation of an innovative screening instru-
ment, named AUTOSCREEN. This instrument, which will consist of the modular iMIC imag-
ing microscopy platform as a future microscopy standard, will integrate ultra-sensitive CCD-
technology and novel software concepts that allow an adaptive, i.e. result-based, shaping
of the ongoing experiment. An ultra-sensitive fluorescence-based scanning device for single-
molecule measurements and a fully automated plate feeder station for automated sample
handling and tracking will increase the flexibility and wide utility of AUTOSCREEN. This
system will be tested in a large number of applications for performance and excellence.
The project is expected to permit the qualitative and quantitative monitoring of cellular con-
stituents (RNA, proteins, and metabolites) in living cells at the highest possible cellular and
subcellular resolution and with maximal sensitivity and specificity. This will allow quantify-
ing protein expression and monitoring its subcellular localisation, its state of modification
and its association with other proteins and ligands. Furthermore, it will allow measuring of
the change of these processes over time.
Potential Impact:
AUTOSCREEN will have a strategic impact on functional genomic, biotechnological and bio-
medical research by permitting qualitative and quantitative monitoring of cellular constituents
in cells at the highest possible cellular and subcellular resolution and with maximal sensitivity
and specificity. This will allow, for example, quantifying protein expression, monitoring of sub-
cellular protein localisation and state of modification, and characterisation of the toponome.
The project will reveal new, faster and better possibilities to determine gene functions and
regulatory networks in a much shorter period of time. The implementation of these technolo-
gies will lead to a higher competitiveness of European biomedical SMEs, in the sense that the
instrumentation to be developed and assembled in this project will enable many European
SMEs to efficiently perform their screens. The estimated low cost of this instrument is expected
to be of great benefit for SMEs as it will promote their market success.
Partners
Project Coordinator:
Prof. Dr. Klaus Palme
University of Freiburg
Institute for Biology II
Faculty of Biology
Center for Applied Biosciences
Fahnenbergplatz
79085 Freiburg, Germany
klaus.palme@biologie.uni-freiburg.de
Scientific/Technological Objectives:
The major objective of TargetHerpes is to define novel drug targets and to identify new
strategies, for the control of herpesvirus infections. These targets and strategies will help, in
the long term, to provide the next generation of antiviral compounds, Specifically, TargetH-
erpes will perform the following actions: (i) develop peptide inhibitors that interfere with
virus entry; (ii) generate synthetic peptides that enable antibody-dependent cellular cytolysis
against herpesviruses; (iii) define, investigate and apply RNA silencing reagents that block
the expression of viral genes that enhance herpesvirus replication; (iv) define, investigate
and apply RNA silencing reagents that interfere with proviral host genes; (v) identify viral
and cellular genes involved in herpesvirus-mediated oncogenesis, and define RNA silenc-
ing reagents and peptide inhibitors; and (vi) develop approaches to inhibit the reactivation
of HSV from latency.
This programme of work will provide innovative technologies for the identification and de-
velopment of future products targeted at preventive and therapeutic interventions for human
herpesvirus diseases. Moreover, these strategies will likely be transferable to many other
persistent infections.
Expected Results:
The TargetHerpes project is divided into six experimental work packages (WPs). The aim of
WP1 is the development of peptide molecules that will inhibit the functions of herpesvirus
glycoproteins and elucidate their roles in entry of the virus particles into cells. Preliminary
work has provided proof-of-principle that mimetic peptides to HSV gH inhibit infection.
Such peptides targeting HSV glycoproteins will be suitable for future animal experimenta-
tion and translational research by partners PRIMM and IBA. WP2 will generate synthetic
peptides that enable IgG antibodies to execute cell-mediated cytolysis against HSV and
HCMV. Such peptides will be evaluated for their individual potency in vitro, then bioac-
tive peptides will be evaluated with regard to safety and harmlessness to cells, as well as
optimal stability in cultured cell systems. WP3, WP4, WP5 and WP6 will identify suitable
molecular targets for antiviral intervention by RNAi.
These targets will include important herpes virus gene products that have known or sus-
pected roles in promoting viral replication directly or indirectly. In case of WP5, siRNAs
100 From Fundamental Genomics to Systems Biology: Understanding the Book of Life
Molecular intervention strategies targeting
latent and lytic herpesvirus infections
targeted at viral genes will be selected based on their capacity to interfere with HHV-8 me-
diated cell transformation and immortalization. WP6 expects to identify the cellular interac-
tion partners of ICP0 (the viral protein that is necessary for HSV to reactivate from latency),
and to define those elements that are required for its activity.
Potential Impact:
TargetHerpes will identify novel strategies, leading to the development of new approaches
to inhibit replication of, or pathogenesis caused by, HSV, HCMV and HHV-8. Due to the
conservation of genes and replication strategies within herpesviruses, the approaches dis-
covered will be applicable to other human herpesviruses as well. For example, treatments
that target HSV-1 are highly likely to be effective against HSV-2 and may be adapted to
counteract varicella zoster virus (VZV). Similarly, treatments that are effective against HHV-8
may also be applicable to Epstein-Barr virus (EBV). Given the figures on the health burden
and costs of herpesvirus infections, the potential impact of a successful outcome of the Tar-
getHerpes project is considerable.
Keywords:
herpesvirus; chemiotherapeutics; herpes simplex virus; human cytomegalovirus; human her-
pesvirus 8; fusion; glycoproteins; siRNA; innate immunity; host response; IFN
Partners
Project Coordinator:
Prof. Gabriella Campadelli-Fiume
University of Bologna
Centro Interdipartimentale Galvani (CIG)
via S. Giacomo 12
I-40126 Bologna, Italy
gabriella.campadelli@unibo.it
Dr. Michael Nevels
Dr. Roger Everett University of Regensburg
Medical Research Council Institute for Medical
Virology Unit Microbiology and Hygiene
Glasgow, UK Faculty of Medicine,
Molecular Virology Unit
Prof. Hartmut Hengel Regensburg, Germany
University of Duesseldorf
Institute for Virology Dr. Angela Pontillo
Düsseldorf, Germany PRIMM Srl
Milan, Italy
Dr. Joachim Bertram
IBA GmbH Dr. Ivan Rossi
Göttingen, Germany BioDec Srl
Bologna, Italy
Dr. Frank Neipel
University of Erlangen Wolfgang Laepple-Boettiger
Institut fuer Klinische ARTTIC S.A.
und Molekulare Virologie Office Mannheim
Erlangen, Germany Schifferstadt, Germany
From Fundamental Genomics to Systems Biology: Understanding the Book of Life 101
FGENTCARD
www.fgentcard.eu
State-of-the-Art:
Project Type: The general aim of FGENTCARD is to apply functional genomic and genotyping technolo-
SME-Specific Targeted gies along with the knowledge arising from mammalian genome annotations, in order to
Research Project define novel diagnostic tools for risk factors of Coronary Artery Disease (CAD) (glucose
Contract number: intolerance, insulin resistance, hypertension, dyslipidaemia and obesity). FGENTCARD,
supported by available functional genomic technologies, will tackle these increasingly fre-
LSHG-CT-2006-037683 quent and prevalent inherited diseases. The project will ultimately generate fundamental
Starting date: knowledge on the impact of functional genomics to identify disease biomarkers and test
1st January 2007 their use for disease prediction. The consortium is interested in focusing on CAD because
Duration: of its frequency and prevalence in the general population, the strong impact on human
36 months health and the burden of related healthcare costs. Pathological elements of CAD have been
shown to have complex etiology and pathogenesis that influence an individual’s relative
EC Funding: risk of developing these diseases. The genetic input is complex, and involves combinations
`3 000 000 of multiple genes that contribute to susceptibility or resistance to CAD risk factors. In order
to take advantage of high density multimodal phenotyping, the consortium is preparing an
innovative infrastructure of both the techniques and materials that provide strategic support
for CAD quantitative genetics in rodent models and humans.
Scientific/Technological Objectives:
One of the major objectives of the FGENTCARD is to identify biomarkers associated with
CAD risk factors, by means of network biology that can be used as disease prediction tools in
clinical studies and as targets for developing novel and more efficient drugs.
FGENTCARD is objective-driven research which develops along the following lines:
1) Characterization of CAD phenotypes, using classical physiological and biochemical
methods in a large cohort of patients and in animal models;
2) Generation of functional genomic quantitative trait datasets using plasma and urine
metabonomic profiling in animal models and humans, plasma proteomic profiling in
animal models and humans and tissue transcriptomic, proteomic and metabonomic
profiling in animal models;
3) Genetic studies which aim at testing the association between plasma biomarkers and
CAD risk factors in humans, at testing the inheritance of plasma, urine and organ
biomarkers in animal models and at identifying underlying gene variants in animal
models and humans.
Close interactions with external international groups investigating related disorders in other
models and human cohorts will provide resources for extension and validation of CAD biomar-
kers. In addition, interactions with other EC funded programmes of research, including MOL-
TOOLS and MOLPAGE, will maximize the scientific and technical outputs of FGENTCARD.
Expected Results:
The consortium plans to deliver the following specific results:
1) Multimodal phenotyping in a novel collection of 5,000 CAD patients, and in mouse
and rat models of spontaneous and experimentally-induced pathologies relevant to
CAD risk factors;
2) A series of integrated functional genomic datasets defining biomarkers associated
with CAD risk factors, through quantitative genetic studies in experimental crosses
derived from animal models and further genetic association and linkage studies in
humans;
3) CAD susceptibility loci and genes providing chromosomal targets for positional clon-
ing experiments and entry points to the development of novel drugs designed for
specific protein and metabolite disease biomarkers;
102 From Fundamental Genomics to Systems Biology: Understanding the Book of Life
Functional GENomic diagnostic Tools
for Coronary Artery Disease
4) A set of standard operation procedures (SOPs) for the characterization of novel CAD
quantitative biomarkers, applicable to genetic and clinical studies in other cohorts of
patients and controls.
5) Data analysis using bioinformatics and statistical genetic tools developed in experi-
mental populations and human cohorts, which will further strengthen the impact of
comparative genomics in biomedical research.
Potential Impact:
FGENTCARD brings together a comprehensive set of specific expertise in functional ge-
nomic technologies (metabonomics, proteomics, transcriptomics), genotyping methods and
statistical genetics in rodent models and humans. This multidisciplinary approach is neces-
sary when undertaking an integrated functional genomic approach that addresses genetic
variation, in the context of CAD risk factors.
Overall, the potential wealth of information that can be obtained on gene expression, from
transcription to protein effects, is enormous. It represents novel challenges in quantitative
genetics, and ultimately, significant advances for disease diagnosis and prevention as well.
An important goal of this research in CAD patients and animal models lies in disease gene
identification. Knowledge of the effects of genetic variations on metabolic processes and
metabotype regulation will have a major impact in the field of polypharmacology, on the
development of novel drugs designed to affect multiple targets simultaneously.
Partners
Project Coordinator:
Dr. Dominique Gauguier Dr. Ulla Grove Sidelmann
University of Oxford NovoNordisk A/S
Wellcome Trust Centre Malov, Denmark
for Human Genetics
Roosevelt Drive Dr. Jorg Hager
Oxford, OX3 7BN, UK IntegraGen SA
gdomi@well.ox.ac.uk Evry, France
From Fundamental Genomics to Systems Biology: Understanding the Book of Life 103
MODEST
State-of-the-Art:
Project Type: The pharmaceutical industry is highly interested in using primary cells instead of cell lines
SME- Specific Targeted for cell-based screening campaigns in drug development since primary cells are freshly
Research Project isolated from the organism’s tissue, and have not gone through any transformations, which
Contract number: is the prerequisite for the unlimited growth of conventional cell lines. With more predictive
screens in terms of both the relevance of a target and the pharmaco-kinetics/-dynamics of a
LSHG-CT-2007-037291 drug compound, it becomes much easier to make adequate decisions as to which targets or
Starting date: compounds to focus on for further development. While conventional transfection methods,
1st April 2007 such as lipofection or electroporation, usually yield satisfactory results for standard cell lines,
Duration: many other cell lines — as well as most primary cells — are difficult or even impossible to
36 months transfect with these methods. Viral vectors - as an alternative for DNA delivery - work well
in some cases, but are labour-intensive, not versatile, and remain connected with significant
EC Funding: safety issues. As a consequence, most primary cells are considered non-transfectable. This
`2 755 356 represents a tremendous disadvantage in highly relevant research areas, as primary cells
are the ones that most closely resemble the situation of the living organism.
Besides the delivery of DNA, RNA or small molecules to primary cells, throughput of trans-
fection experiments is of extreme importance. The emerging RNA interference (RNAi) tech-
nology, continued growth of (drug) compound libraries, and the increasing number of po-
tential targets to be screened, have resulted in the high pressure to increase the throughput
of screening to higher formats, the so-called ultrahigh-throughput screening (uHTS). How-
ever, cell-based assays still use the 96- or occasionally the 384-well format and screening
of millions of compounds may take months instead of days.
Scientific/Technological Objectives:
The principle objective of the MODEST project is the development and use of an ultrahigh-
throughput device for nucleofection (uHTN device) as well as protocols for highly efficient,
small volume ultrahigh-throughput screenings of primary cells, mainly in the areas of immunol-
ogy, neurology and liver metastasis with the aim of accelerating basic research, target identi-
fication and validation as well as drug development.
These uHTN device will represent a major breakthrough, since it would allow high-throughput
screenings in efficiently transfected and differentiated networks of primary cells. In addition,
the concept of disposable modular multi-well plates for transfection is perfectly suited for pre-
plating substances, for storage and for later use, thus allowing flexible approaches, e.g. for
high-throughput screening campaigns.
Application of these tools is planned in order to investigate medically highly relevant disor-
ders. On the basis of the 96-well Nucleofector, which was launched by “amaxa” in 2006,
the Consortium will develop ultrahigh-throughput devices. In parallel, protocols for cultivating,
differentiation, nucleofection and functional screens of primary cells in very small volumes will
be elaborated on and, furthermore, adapted to the devices.
104 From Fundamental Genomics to Systems Biology: Understanding the Book of Life
Modular Devices for Ultrahigh-throughput
and Small-volume Transfection
The scientific knowledge of the MODEST project shall be published in premium peer-re-
viewed journals, and scientists involved in the project will present their data at national and
international conferences.
Potential Impact:
The partners of MODEST will employ the results of the project to service pharmaceutical
customers who repeatedly have expressed the urgent need for devices, protocols and as-
says for primary cells or differentiated human neuronal stem cells in target discovery and
validation. The results of the project will give the partners a clear competitive advantage.
The use of primary cells in preclinical R&D will positively impact attrition rates and reduce
the significant time and capital involved in drug development. The proximity to European
pharmaceutical research and the size of the international pharmaceutical research market
strengthen the logic for the creation and implementation of the MODEST project.
Keywords:
nucleofection, primary cells, hard-to-transfect cell lines, RNAi, siRNA, ultra high throughput
transfection, adult stem cells, neuronal cells, apoptosis, lead, gene silencing/knockdown,
screening
Partners
Project Coordinator:
Dr. Birgit Nelsen-Salz
Amaxa AG
Nattermannallee 1
50935 Cologne, Germany
Birgit.nelsen-salz@amaxa.com
Helmut Loibl
FOTEC Forschungs- und Technologietransfer GmbH
Wiener Neustadt, Austria
From Fundamental Genomics to Systems Biology: Understanding the Book of Life 105
1.2
TOOLS & TECHNOLOGIES FOR
PROTEOMICS
INTERACTION PROTEOME
NEUPROCF
CAMP
ProDac
INTERACTION PROTEOME
www.interaction-proteome.org
Project Type:
State-of-the-Art:
Integrated Project The main objective of the INTERACTION PROTEOME project is the establishment of a broad-
Contract number: ly applicable platform of routine methods for the analysis of protein interaction networks
in biomedical research. A multidisciplinary approach will address different aspects of the
LSHG-CT-2003-505520
generation of protein-interaction data, their validation by cell biological, biochemical and
Starting date: biophysical methods, their collection in a new type of public database and their exploitation
1st January 2004 and use for in silico simulations of protein-interaction networks.
Duration:
66 months These goals represent substantial state-of-the-art advances in these technologies. The innova-
tions generated in INTERACTION PROTEOME will thus provide the basis for an efficient
EC Funding: analysis and systems modelling of fundamental biological processes in health and disease.
`11 999 527
More specifically, INTERACTION PROTEOME will develop novel technologies, including a
high-end mass spectrometer with an extremely large dynamic range, high-density peptide ar-
rays and improved visualisation technology for light and electron microscopy. These technolo-
gies will be validated through model systems of great relevance to medicine and biotechnol-
ogy. In order to cope with the massive increase in experimental data on protein interactions
obtained by using the novel technologies, extensive bioinformatics support will be a key
element in facilitating this work. In particular, the efficient integration of disparate data sets
represents a vital challenge in proteomics and functional genomics.
Within the context of interaction data already included within the scientific literature written
by a community of ‘traditional biologists’, the analysis of the newly discovered interactions
will represent an essential prerequisite for the success of the consortium. For this purpose,
the consortium includes the creation of the only European protein-interactions database,
called MINT.
Scientific/Technological Objectives:
The aim of INTERACTION PRO-
TEOME is to establish Europe as the
international scientific leader in the
field of functional proteomics, and in
particular in the analysis of protein-
protein interactions. One of the major
Localisation of proteins within a objectives includes the establishment
cell: Protein complexes (coloured) of a broadly applicable platform of
are depicted at various levels of routine methods for the analysis of
resolution in their cellular context protein interaction networks.
(background). This technology
enables the visualisation of the The interaction partners of more
3-dimensional architecture and than 100 relevant protein domains
supramolecular structure of cells. and more than 3,000 peptides will
be characterised using these novel
technologies, while the data obtained during the project will be collected in an improved
version of the European MINT database. At the same time, novel bioinformatics tools for
the prediction of protein interactions and their relation to post-translational modifications
will be created. In addition, software for in silico modelling of protein interactions will be
developed and validated with the projects’ model systems.
108 From Fundamental Genomics to Systems Biology: Understanding the Book of Life
Functional Proteomics:
Towards defining the interaction proteome
Expected Results:
The aim of INTERACTION PROTEOME is to establish ground-
breaking technology for the analysis of protein-protein inter- Visualisation of the cytoskeleton
actions. During the first two years of the project, major goals of a Dictyostelium cell. Colours
have already been achieved. were subjectively attributed
to mark the actin filaments
In terms of technology, a major breakthrough by INTERAC- (reddish); other macromolecular
TION PROTEOME was the development of a novel mass complexes, mostly ribosomes
spectrometer, the LTQ-Orbitrap, and its introduction to the (green); and membranes (blue).
market in June 2005 by the project partner Thermo Electron
(Bremen). The Orbitrap is the first fundamentally new mass analyser in more than 20 years.
Compared to a state-of-the-art high performance mass spectrometer (LTQ-FT), the Orbitrap
exhibits a 10-fold increase in sensitivity along with a four-fold extension of the dynamic
range. Based on highly accurate mass determination combined with high resolution and
sensitivity, the novel instrument not only allows for routine analysis with high-throughput,
but also for straight forward analysis of peptide mixtures without chemical or enzymatic
modifications.
From a methodological point of view, the Orbitrap is the ideal instrument for the two novel
“2D-Gel-free” proteomics approaches developed within the project, namely the “SILAC”
(Stable Isotopic Labelling by Amino acids in Cell culture) technology developed by the team
of Matthias Mann at the University of Odense/Max Planck Institute of Biochemistry, Mar-
tinsried, and the “COFRADIC” (COmbined FRActional DIagonal Chromatography) created
by the team of J. Vandekerckhove from Flanders Interuniversity Institute of Biotechnology,
Ghent. Both technologies have been successfully applied to a number of the project’s model
systems, including, among others, the analysis of protein processing in apoptosis by COF-
RADIC, as well as the analysis of Chaperone-dependent protein folding and of signalling
(de)differentiating stem cells by SILAC.
In the first two years of its existence, INTERACTION PROTEOME has published over 30
peer-reviewed publications in internationally renowned journals. During the project’s mid-
term review in December 2005, external experts evaluated INTERACTION PROTEOME
as a clear “showcase project for EU research”. By the end of year four of the project, the
number of publications issued has risen up to 120.
From Fundamental Genomics to Systems Biology: Understanding the Book of Life 109
INTERACTION PROTEOME
In terms of human resources, the impact of INTERACTION PROTEOME in the many ex-
panding areas of biomedicine will be considerable. Young scientists involved in the project
will acquire multidisciplinary skills, including training in bioinformatics, and will thus rep-
resent a valuable resource for the growing biomedical and biotechnological industry. In
addition, highly qualified technical personnel in this novel interdisciplinary research field
will become available through the project. Finally, administrative staff involved in the
management of this large EU project will gain experience for future careers as managers
of international projects.
Phototaxis in Halobacterium
salinarum. A) Halobacteria are
repelled by blue light (left) and
attracted by orange light (right).
B) Components of the halobacte-
rial signal transduction chain
modulating clockwise (CW) and
counterclockwise (CCW) rotation
of the flagellar motor.
110 From Fundamental Genomics to Systems Biology: Understanding the Book of Life
Functional Proteomics: Towards defining the interaction proteome
Partners
Project Coordinator: Prof. Luis Serrano
Prof. F. Ulrich Hartl Centre De Regulació Genómica (CRG)
Max-Planck-Institute of Biochemistry Systems Biology Research unit
Department of Cellular Biochemistry Barcelona, Spain
Am Klopferspitz 18
82152 Martinsried, Germany Dr. Philippe Bastiaens
uhartl@biochem.mpg.de European Molecular Biology Laboratory (EMBL)
(EMBL)-Heidelberg
Project Manager: Cell Biology and Cell Biophysics Programme
Dr. Anne Katrin Werenskiold Heidelberg, Germany
Max-Planck-Institute of Biochemistry
EU Project Acquisition & Management Dr. Mike Schutkowski
Am Klopferspitz 18 JT Peptide Technologies
82152 Martinsried, Germany Berlin, Germany
proteome@biochem.mpg.de
From Fundamental Genomics to Systems Biology: Understanding the Book of Life 111
NEUPROCF
State-of-the-Art:
Project Type: In the search for new diagnostic and prognostic biomarkers for the development of new
Specific Targeted drugs for cystic fibrosis (CF), the identification of new low- and medium-abundance pro-
Research Project teins involved in its pathophysiology is a very promising field. The characterisation of such
markers requires the development of several high performance techniques and the crea-
Contract number:
tion of standards for these new approaches. Several ways will be explored to bring new
LSHG-CT-2004-512044 knowledge to the CF community, applying and developing state-of-the-art mass spectrom-
Starting date: etry, chromatography and electrophoresis methods to the inflammation mechanisms in CF,
1st July 2005 interaction between proteins, mainly the cystic fibrosis transmembrane regulator (CFTR),
Duration: and other molecules, like DNA, other proteins or lipids. In addition to the biomarkers, this
should bring a better understanding of CF pathophysiology with regard to transepithelial
36 months ion transport, inflammatory processes and the identification of factors responsible for the
EC Funding: different CF phenotypes.
`2 355 000
Scientific/Technological Objectives:
The aim is to identify new low abundance protein biomarkers in serum. In the meantime,
the project will generate new basic knowledge for inflammation, protein-, lipid- and DNA-
interaction in all fields related to scientific fields, such as cancer, neurodegenerative dis-
eases and asthma that are considered as priorities for EC science.
Another strategic impact concerns prognostic biomarkers: the phenotype of CF is quite vari-
able, even in patients bearing the most frequent mutation delta F508. To tackle the prob-
lems posed by this disease and to try to decipher the underlying mechanisms, large-scale
studies at the protein level would certainly accelerate discoveries, in particular by detecting
low abundance proteins. This will imply new standard protocols for sample collection and
technologies by:
s DEVELOPING AND APPLYING HIGHLY SENSITIVE METHODS FOR PROTEIN IDENTIlCATION BY -3
which will be useful for the proteomic community;
s DEVELOPING AND APPLYING HIGHLY SENSITIVE METHODS FOR THE IDENTIlCATION AND QUANTIl-
cation of lipid molecules which interact with CF-related proteins;
s APPLYING THESE TECHNOLOGIES TO IDENTIFY #&
ASSOCIATED PROTEINS AND LIPIDS INVOLVED IN
pathogenesis of CF;
s INTEGRATING THE DATA IN A COMPREHENSIVE DATABASE USEFUL FOR #&