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 science. 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 functional level. At the same time this research gives rise to interesting and challenging problems at the frontier of theoretical physics.

Transcriptional and epigenetic mechanisms of cell fate regulation

The self-organisation of cells during the development and maintenance of tissues is one of the most intriguing non-equilibrium processes in nature. How do cells coordinate their behaviour in order to build a complex structure like a living organism? The ability to self-renew places stem cells, which have the remarkable capacity to generate multiple cell types in the developing and adult body, at the apex of theories of tissue maintenance and development. To ensure that the correct composition of differentiated cell types is generated at the right time and place, the fate of stem cells must be precisely regulated. Understanding how stem cells regulate their fate is pivotal for understanding diseases that arise due to dysregulation, such as diabetes and cancer, and for the development of stem-cell-based therapies in regenerative medicine.

Recent advances in single-cell genomics and multi-omics for the first time allow quantifying the transcriptome and epigenome on the level of single cells, thereby providing the exciting opportunity to gain mechanistic insight into the molecular processes underlying stem cell fate behaviour. With our collaborators we combine novel single-cell sequencing experiments with methods from non-equilibrium physics to unveil the mechanisms unveiling stem cell fate behaviour on the molecular level.

Example of single-cell bisulphite sequencing data taken from S. A. Smallwood et al., Nat. Methods 11, 817 (2014).

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.


Collecitve cell dynamics in development, maintenance, and disease

 

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.


Genetic diversity and phenotypic heterogeneity

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 and phenotypic heterogeneity evolve in microbial populations. The apparent lack of symmetries in these systems give rise to challenging and interesting questions at the frontier of non-equilibrium statistical physics.