Research

To establish specialised tissues, biological systems rely on a constant flux of energy from their environment and they therefore operate far from thermal equilibrium. The ensuing phenomenology often is highly complex such that a deep going understanding poses significant challenges to theoretical physics. By collaborating with experimental groups we combine novel experimental possibilities, in particular in single-cell genomics, with the methodology of non-equilibrium physics to unveil the mechanisms regulating stem cell behaviour on the molecular and tissue level. At the same time this research gives rise to interesting and challenging problems at the frontier of theoretical physics.

How do molecules collectively decide the behaviour of a cell?

During development, the differentiation of cells to different lineages is closely associated with the establishment of specific epigenetic marks along the sequence of the DNA. During ageing, temporal changes in these patterns have been found to be tightly correlated to biological age and predictive of the time of death. The mechanistic basis underlying these processes is, however, poorly understood. The recent advent of single-cell sequencing technologies for the first time give the opportunity to probe these processes with unprecedented molecular resolution in vivo. Biological function, however, relies on collective processes on the cellular scale which emerge from many interactions on the microscopic scale. But what can we learn about such collective processes from detailed empirical information on the molecular scale?

Concepts from non-equilibrium statistical physics provide a powerful framework to understand collective epigenetic processes. We combine data obtained from novel single-cell technologies with methods from non-equilibrium statistical physics to understand collective epigenetic processes regulating cellular behaviour during development and ageing.

In plain English

Stem cells play a pivotal role in development and tissue maintenance, as well as the initiation of cancer. In order to build and maintain functioning tissues the behaviour of these cells must be tightly regulated. Understanding how stem cells decide to become more specialised cell types will help harvesting the enormous clinical potential of these cells.

Researchers in the Statistical Physics of Living Systems group apply concepts from theoretical physics to gain mechanistic understanding of how stem cells regulate their behavior on a molecular level and on the level of tissues.


How do biological systems integrate information on different spatial scales?

Cellular systems have the remarkable capacity to build and maintain complex spatio-temporal structures. Striking examples are the formation of complex organs during embryonic development or the response of the tissue after injury. The regulation of these phenomena relies on distinct processes occuring on vastly different spatial scales, from the self-organisation of molecules into subcellular structures to cell-to-cell communication.

We are interested in how biological systems can utilise interactions between processes on different spatial scales to make informed decisions in noisy environments. Apart from cell biological applications, together with our collaborators, we use primitive social insects as a biological model system to address this question.


How do cells self-organise into tissues?

 

The development and maintenance of tissues relies on a tightly balanced coordination of cell proliferation and differentiation. How do these cells collectively build and maintain complex structures such as the heart or the pancreas? With the recent advent of transgenic mouse models we are now in a position to study collective fate decisions on a functional level. On this level, stem cell populations are often considered as an ensemble of statistically equivalent cells, such that the methodology of non-equilibrium physics has been successfully employed to understand their behaviour.

However, major questions in stem cell biology remain elusive: How can we understand the surprising degree of heterogeneity that appears to be characteristic of many stem cell populations? How can we use lineage tracing to understand the morphogenesis of developing tissues, where tissue deformation and cell migration often lead to the fragmentation and merging of labelled clones? To answer these questions we develop theoretical frameworks to facilitate the application of functional assays in novel contexts and to unveil the functional regulation of stem cell behaviour. In collaboration with experimental groups we use these methods to unveil stem cell fate behaviour in various tissues and investigate universal principles of cell fate regulation.


Phenotypic heterogeneity and epigenetic plasticity

A high degree of specialization makes organisms vulnerable to environmental changes. How can organisms specialize to an ecological niche and at the same time be able to survive in a variety of different conditions? Many bacteria and viruses counteract specialization by switching between several phenotypic states, and even stem cell population seem to be much more heterogeneeous than previously thought. As an example, phenotypic switching is a strategy commonly employed by pathogens to evade a host's immune system. Some types of bacteria also stochastically switch between phenotypic states to minimize the risk of population extinction due to an attack with antibiotics, and syncitial stem cells in the murine testis stochastically interconvert between various stages of differentiation. Inspired by these phenomena, we are interested in how genetic diversity, phenotypic heterogeneity and stem cell plasticity are regulated across scales.The apparent lack of microscopic symmetries in these systems give rise to challenging and interesting questions at the frontier of non-equilibrium statistical physics.