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Jens Timmer simulates dynamic processes in the cell

Systems biology is growing in influence around the world. The cell is a dynamic network consisting of thousands of molecules that interact with each other. Only when scientists take into account these constantly changing patterns are they able to develop new ideas for drugs to treat certain disorders. Such developments require the contribution of theoretical physicists like Prof. Dr. Jens Timmer from the University of Freiburg. The researcher showed quite some time ago that mathematical models can reveal relationships that would remain undiscovered if only empirical biological approaches were used. From the very beginning of his career, Prof. Dr. Jens Timmer has focused on the mutual synergy of empiric and theoretical research.

Prof. Dr. Jens Timmer © private

Ten years ago the dogma was: one defective gene, one drug. The belief that only one defective protein needed to be targeted in order to remedy a defective cell was based on the rather rigid picture of cells. Researchers now know that any gene product interacts with a large number of other proteins. For example, external signals that are transferred into the cell and induce reactions in its interior trigger entire networks of molecular changes below the cell membrane. These changes have different temporal courses: the concentrations of molecules change, reach threshold values and drop again. Different temporal courses also lead to different reactions on the genetic level. "We are not able to understand all these processes without mathematics," said Prof. Dr. Jens Timmer, head of the Department of Data Analysis and Modelling of Dynamic Processes in the Life Sciences at the Institute of Physics at the University of Freiburg and director of the School of Life Sciences - LifeNet - at the Freiburg Institute for Advances Sciences (FRIAS). "Mathematical models are today's new method, just like the microscope once was many years ago: mathematical models enable us to see things that we were previously unable to see."

A telephone call with consequences

What kind of things these are can be best explained using Timmer’s acquaintance with systems biology. Timmer, who was born in 1964 in Wolfsburg, studied physics in Oldenburg and Freiburg between 1983 and 1990. He did his doctoral thesis in Freiburg in a research group of the Department of Psychiatry at the Freiburg University Medical Centre. “This was an amazing piece of luck, because it brought me into immediate contact with clinical data,” said Timmer who was originally interested in the chaos theory which focuses on describing dynamic processes such as the weather and the rise and fall of shares using mathematical formulas. However, Timmer realised very early on that new approaches were required in order to explain data gained in EEG studies involving schizophrenia patients. “In Freiburg, right from the outset I was using data from experiments to get ideas for mathematical models,” said Timmer going on to add “I am still doing the same thing today.”

Eleven years ago, Timmer received a phone call from Ira Swameye, a biologist in the group of Ursula Klingmüller at the Freiburg-based Max Planck Institute of Immunobiology. Swameye told Timmer that she had a great deal of data on a broad range of different proteins that she was unable to analyse on her own. “This was in 1999, and I had just habilitated and had a lot of work on,” said Timmer. “I nevertheless decided to get involved and she told me something about biological signalling cascades. Of course, I did not understand what she was trying to explain.” The two researchers met almost every week to have lunch together and explain their respective research areas to each other. Eventually, Timmer decided to develop a model to simulate the dynamics of the simplest signalling pathway known back then: the JAK-STAT cascade.

The temporal course is key

The JAK/STAT cascade is one of the simplest signalling pathways in a cell. © Prof. Dr. Jens Timmer
The JAK/STAT system consists of only four molecules. It is triggered by the hormone erythropoietin (EPO), which is produced in the kidneys and which induces blood precursor cells to develop into red blood cells (erythrocytes). The EPO receptor, which is located in the membrane of the precursor cells, translates the signal into the interior of the cell: once EPO has docked to the receptor, the receptor is in turn activated by so-called Janus kinases (JAK). This then enables STAT molecules to attach to the receptor and become activated. Two activated STAT molecules assemble into a dimer and diffuse into the cell nucleus where they switch the activity of numerous genes on and off. “We translated this simple picture, which initially does not provide any information about the temporal course of the individual reactions, into four differential equations,” said Timmer. “In these equations, different variables can be changed, i.e. enable theoretical changes of certain intermediary products or vary the speed of certain reactions. And then we can show what happens.”

It soon became clear that the biologists had made a mistake in their purely qualitative representation of the processes. “Our model showed that STAT had to leave the nucleus again after six minutes, rather than after half a day as was previously assumed by biologists,” said Timmer. “The findings obtained with our model were later confirmed in laboratory experiments. STAT has a very short-term effect on the genes, something that would not have been detected without the mathematical model.” In the meantime, the Freiburg physicists and the biologists led by Ursula Klingmüller (now at the DKFZ in Heidelberg) have discovered further details relating to the signalling pathway. In a recent publication in the renowned journal Science, the scientists were able to show why blood precursor cells that are flooded with large amounts of EPO after injury are nevertheless able to react sensitively to the hormone. The researchers used the aforementioned mathematical model and carried out numerous experiments in order to come up with these results. Following the binding of EPO to its receptor, the two molecules are quickly taken up into the interior of haematopoietic cells where they are degraded. Newly synthesised receptor molecules are continuously being attached to the cell surface, where they can bind to and react with new EPO molecules.

The successful cooperation between the research groups of Timmer and Klingmüller enabled the cooperation partners to take over the coordination of a subproject of the HepatoSys consortium in 1994. Timmer was the spokesperson of the consortium, which was initiated by the German BMBF, until this year. This large competence network, which involves around sixty research groups, focuses on the systems biology of the liver cell, which plays a key role in many human diseases. The follow-up project, known as “Virtual Liver”, was started in 2010 and focuses on higher liver and organ levels. It is also coordinated by a full-time spokesperson.

The future of medicine?

Prof. Dr. Jens Timmer and his team link mathematics with biology. © Prof. Dr. Jens Timmer

Over the last few years, Timmer and his team have worked on improving and expanding their models. Numerous signalling pathways play a role in cells, and these pathways are far more complex than the JAK/STAT pathway. The MAP kinase signalling pathway is one such complex system, and it plays a key role in the development of cancer. The MAP kinase signalling pathway involves around 24 proteins that interact with each other in a rather complicated way. Timmer and his team suggested a model to simulate the interactions of these proteins. Timmer's department now has around forty members of staff who cooperate with biologists, toxicologists and medical doctors from Freiburg and other cities. Timmer was involved in the establishment of numerous institutions in Freiburg that contribute to the excellent infrastructure of systems biology in Freiburg: for example, the Freiburg Initiative for Systems Biology (FRISYS), the Centre for Data Analysis and Modelling (FDM), the Freiburg Institute for Advanced Studies (FRIAS) and the Centre for Biosystems Analysis (ZBSA). In addition, he is the co-founder of Scientific Consulting Group GmbH established in 1998. In 2007, the company became two separate companies known as seleon GmbH and TNI medical AG.

Further information:
Prof. Dr. Jens Timmer
Institute of Physics
Faculty of Mathematics and Physics
Freiburg, Germany 
Phone: +49 (0)761-203 97447
Fax: +49 (0)761-203 97451
E-mail: jens.timmer(at)frias.uni-freiburg.de
Homepage: https://www.gesundheitsindustrie-bw.dewebber.physik.uni-freiburg.de/~jeti/

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/jens-timmer-simulates-dynamic-processes-in-the-cell