Systems biology deals with the complex biological processes between and within cells, organs or the organism as a whole. The goal is to not only to understand but especially to predict such processes. The work group of systems biologist Dr. Herwig investigates in silico methods, i.e. computer modelling of complex biological metabolic processes (so-called pathways) and the integration of experimental data into these models. Dr. Herwig and his team develop methods for predicting the toxicity of chemical substances, or the toxicity and efficacy of pharmaceutical drugs.




Dr. Ralf Herwig receive the official document from Peter Bleser, Parliamentary Secretary of State in the Federal Ministry of Food, Agriculture and Consumer Protection (BMELV).
Image: Christiane Hohensee


The research is based on the results of so-called microarray studies, obtained from genetic expression analyses or mass spectrometry data. The researchers gathered results on signal pathways from in vitro cell culture models of different organ cell types, for instance after having treated cells or tissues with a test substance. They analyse mass spectrometry data and identify proteins typical to the metabolism of foreign substances or to the development of certain diseases. In this context, observing the interaction of proteins with one another or of proteins with DNA also plays a part. The work group recently developed a databank which documents the interactions between cellular molecules.

The work group develops software and methods in the field of multivariate statistics, as well as concepts in the field of probability theory and other statistical methods. The work group has particular expertise in the modelling of disease processes such as cancer or ageing processes.

This year’s recipient of the Animal Welfare Research Award has not only developed a systems biological method for assessing the carcinogenicity of chemicals in the liver, but at the same a replacement method for experiments on animals - one capable of replacing a great number of animals (especially rodents) in chronic toxicity tests (two-year studies) for the carcinogenicity of chemical substances.


InVitroJobs congratulated the award recipient and spoke to him on the occasion of the award ceremony.

InVitroJobs: Congratulations on receiving the Animal Welfare Research Award.

Dr. Ralf Herwig: Thank you very much.

InVitroJobs: In the context of the development of a systems biological prediction model, there has been some talk of a modern in vitro model using human hepatocyte precursor cells that can test environmental chemicals for carcinogenicity. Did you develop that, too?

Dr. Ralf Herwig: No, we are a solely bioinformatics work group. The in vitro model is a result of the carcinoGENOMICS project funded by the European Union and coordinated by Maastricht University. In vitro models were developed for various organs, such as the liver, kidneys and lungs, and substrates were tested. In collaboration with the Swedish company Cellartis AG (ed.: now Cellectis), an in vitro hepatocyte model was developed using human embryonic stem cells. The result is a “metabolically competent” cell line, i.e. those cells relevant to foreign body metabolism are able to react to being treated with a substance by expressing genes or activating the genetic expression. We can measure this metabolic competence.

InVitroJobs: How are the data collected?

Dr. Ralf Herwig: Central readouts in the project are the transcriptome and the metabolome. We use oligochips developed by the company Affymetrix. On these there are reporters for almost the entire human transcriptome. If you prepare the RNA being investigated with a fluorescent dye, and if genes become activated after applying a substance, you can detect this by means of the fluorescence bonded by the reporters. We found some markers in the genetic expression that were more pronounced and others that were less so. We especially observed the functions of the gene transcripts and we able to determine a high metabolic competence. That way we could identify those genes that play a part in foreign substance metabolism. By means of an analysis of variance (ANOVA model), we were able to identify genes that react to test substances, which we subdivided into three classes (genotoxic carcinogens, nongenotoxic carcinogens, and noncarcinogens as a control group). The greater part of the genes was related to foreign substance metabolism. In order to characterise the function of these response genes, we used a databank developed in the work group, called ConsensusPathDB. This databank contains a great number of human interactions, that is, molecular relationships between these genes; and amongst these we found some that have to do with DNA damage, cancer development and apoptosis. Cancer proteins are important in the context of predicting the carcinogenicity of a test substance. These are proteins that characterise cellular damage when it takes place, e.g. ATM proteins (sensors für double-strand breaks in DNA), metabolic products that indicate programmed cell death and cell cycle proteins, which are all “Hallmarks of Cancer” as described by Hanahan and Weinberg.

In a further work step, we then matched the genes to the corresponding molecular pathways and used these pathways directly to classify the test substances. We were able to demonstrate that this pathway-based approach considerably approves the classification, as opposed to the gene-based approach. This approach has proven to be especially advantageous with regard to nongenotoxic carcinogens that do not primarily alter genetic material, but rather induce their cancer-causing effects via many molecular pathways. Here, for instance, we were able to identify specific pathways for nongenotoxic carcinogenicity (such as fat metabolism).

The method itself is stabile and reproducible, and has already been prevalidated by the ECVAM in a double-blind study.

InVitroJobs: Can you imagine the systems biological approach eventually replacing animal experiments?

Dr. Ralf Herwig: I can imagine that happening in the medium or long term, especially in light of the technological progress we are making in science. Genome sequencing is a good illustration of this: Whereas the Human Genome Project needed about 3 billion U.S. dollars and about 10 years with hundreds of scientists around the world to sequence the first human genome, you can now sequence and analyse a human genome for less than 10,000 U.S. dollars in a few weeks. That means that we will obtain much more precise data on the substances and the cellular systems, which will hopefully lead to predictions from in vitro systems improving, and then replacing—or at least considerably reducing—animal experiments.

InVitroJobs: The PREDICT project you coordinate focuses on individualised cancer therapy. What is currently the greatest challenge in cancer research?

Dr. Ralf Herwig: The main problem is the lack of efficacy in cancer treatment. The main reason for this is the individual mutations of the tumour cells, which lead to therapies being ineffective for certain subpopulations. Recognising these and developing an optimal therapy is the challenge for systems biologists. We now know a lot about patients that we didn’t know ten years ago. Molecular pathways help us to determine whether a mutation is present and the active agent will therefore not have the desired beneficial effect. The challenge is to be able to use predictions to rule out patients before applying ineffective therapies and to arrive at a targeted therapy.

InVitroJobs: What qualifications do students on the lookout for opportunities need in order to become system biologists? Is there now a masters course?

Dr. Ralf Herwig: There are not yet any courses in systems biology as such. System biology is a main subject in the established courses in biology, biophysics or bioinformatics. System biology lies exactly at the interface between biology and mathematics, between system-wide data and their mathematic modelling. What’s important are mathematical understanding, an understanding of dynamic systems, statistics and bioinformatics, knowledge of where genetic data come, and knowledge of biology and medicine.

InVitroJobs: Thank you for talking to us.

Dr. Ralf Herwig: It was a pleasure.


Recommended literature:

Yildirimman, R. Et al (2011): Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for In Vitro Hazard Assessment of Chemical Carcinogenicity. Toxicological Sciences 124 (2): 278-290. (doi:10.1093/toxsci/kfr225)
Hanahan, D. & Weinberg, R. A. (2000): The Hallmarks of Cancer. Cell 100: 57-70.

Also of interest:

carcinoGENOMICS project: http://www.carcinogenomics.eu
Molecular interactions databank: http://ConsensusPathDB.org