It only takes a few genes make the deadly enterohaemorrhagic form of Escherichia coli (EHEC) that is so dangerous to humans. If it were not for these genes, EHEC would hardly differ from the harmless (and indeed, useful) form of the bacterium which occurs naturally in the gastrointestinal system.
Bioinformatics specialists from the Saarbrücken Cluster of Excellence aim to exploit this similarity to find starting points for effective drugs against the EHEC pathogen. They have constructed EhecRegNet, a database and analysis platform that incorporates all known interactions between the genes of E. coli bacteria found in the human digestive system. Using integrated simulations, genetic switches for the dangerous EHEC genes can be identified much faster, and applied to drug development.
All humans carry roughly one to two kilogrammes of bacteria in their bodies. As the most common enteric bacterium E. coli, is also the best-studied microorganism on earth. “It’s genetic composition has been documented in detail and we know of around 3,500 gene interactions, that is, around 40 per cent of the regulatory processes that go on in the bacterium,” says Jan Baumbach, who heads a research group at the Cluster of Excellence for computer science at Saarland University.
Together with his team at the Max Planck Institute for Informatics in Saarbrücken, Baumbach quickly realised that the EHEC pathogen that is responsible for the current outbreak in Germany is closely related to normal intestinal bacteria. “We assume that no more than ten genes make the EHEC pathogen life-threatening. Some genes emerged a long time ago, over the course of evolution, but others were modified through an inter-bacterial exchange of plasmids. It is a kind of primitive sex that the bacteria use to transmit genetic information. This often leads to resistance to antibiotics,” Baumbach said.
His research team has put all the information on the harmless enteric bacteria’s genome and interactions in a database, which also lists the genetic data of the dangerous EHEC pathogen. On the computer, the EhecRegNet system compares the genetic data of the EHEC bacteria with the data from harmless bacteria to track down genetic switches in EHEC. The goal is to use these switches to disable the genes that cause severe renal failure in some patients.
“Genes can be switched on and off, much like a light bulb. But first you have to find the right switch. At the moment, you could say that we are throwing stones at the light bulb to put out the light. We still do not know where the switches are for EHEC, but we do know where they are located in related harmless bacteria. That is our starting point,” says Baumbach.
Knowledge of around 80 to 90 per cent about interactions in normal enteric bacteria can be transferred to the EHEC pathogen by utilising the computer simulations. This knowledge about harmless bacteria has been gathered by biologists and medical scientists over the last twenty years. “We cannot afford to be spending so much time with the EHEC bacteria, but we can take a short cut and use the available information about harmless bacteria and transfer knowledge about their genetic regulation to EHEC. It will save us time-consuming, expensive and even dangerous work in the laboratory,” says Baumbach.
The Saarbrücken scientists are offering free access to the EhecRegNet web platform, in order to involve all biomedical scientists and pharmacists around the world in the search for drugs against the EHEC pathogen.
Baumbach’s research group at the Saarbrücken Cluster of Excellence “Multimodal Computing and Interaction” at Saarland University has already constructed similar web platforms for corynebacteria which, among other things, trigger diphtheria, and for tuberculosis.
The new database and analysis platform for E. coli and EHEC gene Regulatory Networks can be found at: www.ehecregnet.de