Interview with Nils Blüthgen

In May, Nils Blüthgen and his team were awarded with the Paper of the Month for their open access publication in which they study the ERK signal path by means of mathematical modeling. The publication emerged from the TRG project “Systems Medicine of BRAF-Driven Malignancies.” We interviewed him about his research and the project.

What is at the focus of your research?

Millions of cell divisions take place in the human body every second. At the same time, millions of cells actively die in programmed cell death (apoptosis), for instance to make room for new cells or to prevent uncontrolled growth. The decision whether a cell divides or dies is communicated by the body’s growth signals. In our research, we are attempting to understand the principles of how cells in our body interpret the growth signals and then make decisions about their behavior. To do this, we are using a combination of modern experimental processes to obtain molecular data, and computer models with which we can analyze this data and simulate the cell’s behavior on the computer.

What motivates you to perform this research? 


There are a series of factors that motivate my team and me. For one thing, it’s simply exciting to study such fundamental processes and to acquire better understanding of the fundamental principles of life. What’s more, it is highly relevant to understand these processes more accurately, since it’s precisely these processes that are disrupted in many diseases, and especially in cancer.

What is the essence / core message of your publication, and how does your study differ from the work of other scientists in this field? 


In our publication, we took a closer look at the question of what mechanisms cells use to differentiate short-term growth signals – such as those necessary for wound healing – from chronic growth signals. In healthy bodies, chronic growth signals lead to programmed cell death in the affected tissue, while they can contribute towards the development of cancer in case of disease. What this means is that many types of cancer develop strategies to bypass programmed cell death and thus enable uncontrolled growth. So we’re investigating the question of how cells process and interpret the body’s short-term and chronic growth signals. In our research, we discovered a class of genes that are able to interpret the body’s growth signals and translate them into a cell response. In other words, the genes can help the cells to differentiate short-term growth signals from chronic ones. It turns out that the most important thing for differentiating signals is the rate at which the gene products decompose. For example, we learned that especially long-lasting, stable gene products become more and more enriched the longer the growth signal lasts. In healthy cells then, the enrichment of these genes can lead to programmed cell death as a response to the chronic growth signal. In cancer cells, however, additional signal paths are activated that prevent the long-lasting genes from being enriched. 

Which partners did you collaborate with for the publication? Who were the major contributors to the work? 


The work was carried out in close collaboration with Markus Landthaler’s research group at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and was made possible by a Twinning Research Grant (TRG) from BIH. Together with Markus Landthaler and Emanuel Wyler, we were able to develop and utilize new kinds of experimental methods in this project with which we could precisely determine the decomposition rates of the gene products that come to bear here.

What are the next steps planned for the project, and what are the possible implications of your findings for patients? 


The decisive factor is that the class of genes that are activated through chronic exposure to growth signals – the way it can occur in a tumor as well – all generate long-term gene products, and they are therefore fundamentally distinct from others with only short-term exposure. But what are the principles and processes that cause these differences? Can these processes be controlled with medications? Finding this out will be the next step. What’s more, it will now be exciting to see whether and how tumors shut down these genes and curb their effect and whether it is possible to reactivate these genes – which often convey cell death – through targeted interventions or medications. This in turn could present new therapy options. But that’s still a long way off!