The DIAMONDS project

DIAMONDS - Dedicated Integration And Modelling Of Novel Data and prior knowledge to enable Systems biology

The overarching objective of this multidisciplinary Specific Targeted Research Project is to demonstrate the power of a Systems Biology approach to study fundamental biological processes. We focus on eukaryotic cell cycle regulation, and will develop and implement a computational model that will function as a hypothesis-generating engine in a systems biology ‘wet-lab’ environment. The work will be done in a number of wet-labs and dry labs, on yeast, plant and human cells, to make sure that the approach is validated across widely different organisms. The main target of the project consists of two parts: a cell cycle knowledge base and an integrated platform of data mining, modelling and simulation tools that will allow the integrated analysis of that data in a Systems Biology approach: the development of a basic model, the use of this model to design new experiments, the production and analysis of novel data and the integration of these into a refined model. The knowledge base and tools will be made available and introduced to the European research community.

The major means to reach this target is to harvest and/or produce a large body of cell cycle related biological knowledge. This will function as the central resource for the modelling and simulation environment that will be developed. As mentioned above, the knowledge warehouse will constitute one of the major deliverables of the project, enabling future hypothesis-driven research. The project will showcase the fact that a Systems Biology approach toward analysis of a fundamental biological process can in fact become mature today, and hinges on an integrated data analysis pipeline, extended with modelling and simulation tools. Essential elements of such a pipeline will be: functional genomics data production (transcriptome and proteome); literature mining; comparative analysis of genes and networks; a visualisation, modelling and simulation environment, and a web service based data integration layer.

The core set of models includes:

1) Saccharomyces cerevisiaea (budding yeast)

2) Schizosaccharomyces pombe (fission yeast)

3) Arabidopsis thaliana (weed, dicot model plant)

4) Homo sapiens (human)

To deliver a knowledge base for future cell cycle control research.
Present a showcase example for a Systems Biology approach in a variety of eukaryotes.
Design a mathematical model of cell cycle networks on the basis of genome wide data sets.
Produce a Systems Biology data integration and modelling environment.
Identification of Cell Cycle targets of major signalling pathways affecting cell division.
Initiate validation of these targets through exploration of perturbations (mutants, small molecules) in wet-lab experiments.

DIAMONDS will make use of a number of established technologies developed for genome wide applications, and it will combine them such that we assemble a large toolset to perform a comprehensive mining of a broad array of data types for patterns, annotations and other parameters embedded and associated with these. Because we primarily use existing technologies we do not expect major problems. The prospect of being able to optimise several of the technologies specifically for their application on cell cycle modelling makes us even more confident that we can achieve our objectives. Technologies include the analysis of the transcriptome, targeted proteomics approaches (including the analysis of the dynamics of protein modification), and integration with prior knowledge from literature (text mining approach) and annotated databases. The combined data will be integrated into rigorous dynamical models that will be progressively refined through subsequent in silico (simulations) and experimental validation. Again, the core foundation for this already exists, and will be further refined and most importantly filled with curated data in the course of the project. The components of the regulatory networks identified will be systematically questioned for amenability to chemical perturbation (modification, inhibition or blocking) of the cell cycle, both to assess the potential for drug design, their involvement with crop growth characteristics and in general their fundamental role in the regulatory system.

DIAMONDS is conceived as a first step towards the development of the Systems Biology of the cell cycle. The successful implementation of this project will create a firm basis for a high-throughput functional analysis of findings and hypotheses, and it will present a case example for Systems Biology in higher eukaryotes. While the project is aimed at the implementation of advanced approaches to further our understanding of cell cycle control, the project may also provide the trigger for such integrated approaches of data collection and modelling to unravel other fundamental biological processes. We choose cell cycle regulation because it is of particular significance for human health:

Disturbances of the cell cycle regulatory network lie at the basis of many cancer types.
The comparative approach will illuminate the variation in the intrinsic stability of cell cycle controls in plants and animals, what may lead to new insight into how to combat proliferative disorders.
The analysis of the mode of action of cell cycle regulators will provide a basis for identification of potential therapeutic targets.
The use of a cell cycle simulation model may help predict the value of putative therapeutic components.