From a set of formulas to visible changes in liver cancer

Systems Biology is a young field with the overall aim of creating a holistic picture of dynamic life processes with regard to all levels – from the genome via the proteome and the organisation of the cell organelles all the way to the complete cell or even an entire organism.

In doing so, Systems Biology takes into consideration the dynamic interplay of the components involved. In order to achieve this high aspiration, Systems Biology combines quantitative methods used in molecular biology with knowledge gathered in mathematics, informatics and systems science.

The HepatoSys consortium was launched in 2004 as the first large and interdisciplinary network in the field of Systems Biology. Since then, more than 40 research groups all over Germany have applied themselves to the investigation of molecular- and cell-biological processes in the liver cell (hepatocyte). “In the course of the last few years we have laid the foundation for a systems biology investigation of hepatocytes”, says CancerSys coordinator Prof. Dr. Jan Hengstler of the University of Dortmund.

Computer models for the simulation of signal transmission pathways were developed as well as standardized cell culture conditions and common process specifications to form a base for quantitative analysis of the processes within the cell and also for interdisciplinary collaboration. “On this basis, we can now turn toward more specific questions such as the processes involved in the evolution of liver cancer”, explains Dr. Hengstler who has a leading part in the HepatoSys network as the coordinator of the cell biology platform.

CancerSys is aiming at two particular signal paths known to play a role in the development of cancer if they get out of control, namely, the beta-catenin- and the ras-signal paths. Both regulate the reproduction (proliferation) of liver cells and have an influence on their gene activity. The beta-catenin-path is particularly relevant in the center of the lobe of the liver whereas the ras-signals are dominant in the periportal area, i.e. close to the portal vein which is the gateway for blood entering the liver.

The objective of the CancerSys consortium is to construct dynamic models of these two signal paths and their interaction and to then integrate them into a three-dimensional simulation of the liver. “We created mathematical models on the basis of quantitative molecular- and cell-biological tests and then built a bridge from this set of formulas to the visible changes caused by the cancerous process in the liver”, Hengstler said, in explaining their research objective. By means of this hitherto unique methodical approach, it is possible to graphically reconstruct which consequences a change – i.e. through gene mutations, viral diseases or toxic substances such as alcohol and certain medications – involves in the network of signal paths and can thus contribute to the development of cancer. Impressive first simulations can be viewed at http://inria.livertumor.hoehme.com.

The CancerSys research project was given the highest possible rating by the European Union brain-trust and is expected to take up work early in 2009. In the first instance, nine project partners with their research groups are participating. Four of them will work experimentally, four will work theoretically and one will work in both modes. Most of the research teams involved are from the HepatoSys consortium as well as from other German systems biology networks. International groups from Europe and the US will also take part. “Not only do we expect substantial progress from the network on the subject of liver cancer,” says Hengstler. “CancerSys also signifies an expansion and better visibility for German systems biology research, especially for HepatoSys, on an international level”. Thus the activities of CancerSys will have positive effects on Germany as a research location.