The more complex a machine is - the more likely it is to break, simply because there are more potential breaking points. Yet, cells are highly complex entities and are extremely robust. We want to understand the underlying basis: what makes biological systems reliable? Which design principles are used? Do they resemble the principles that humans use in engineering? 

To study these questions, we look at cell division, a process that is essential for life. When cells divide, a multitude of changes need to happen in a very short timeframe, and any error can be fatal. Hence, reliability is crucial. We use fission yeast in our experiments to identify general principles that have made cells successful in populating the earth for the past 3.5 billion years. 


The mechanism of spindle assembly checkpoint signaling

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When cells divide, they need to pass on copies of the genetic information to both daughter cells. This step is controlled by a signaling pathway called the spindle assembly checkpoint. If the checkpoint fails, cells can become aneuploid, i.e., have the wrong number of chromosomes, which is a condition associated with cancer. We study how the checkpoint signaling network is constructed and which features allow it to work reliably. 


How do cells keep protein levels and noise within an acceptable range? 

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Biochemical reactions inside cells are fundamentally stochastic, i.e. a reaction occurs when two molecules encounter each other. If molecules are present in many copies, this happens frequently. However, in reactions that involve genomic DNA (1 or 2 copies per cell) or mRNA (often only a few copies per cell), this causes considerable variability and results in fluctuations of mRNA and protein abundance (called 'noise'). We want to know how cells keep noise in check and produce just the right amount of a given protein. We study this in the context of the spindle assembly checkpoint, where we know that precise protein concentrations are important for proper function.  


How are cellular processes appropriately timed and coordinated with each other? 

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The separation of the chromosomes in anaphase is one of the most dramatic events of the cell cycle. The separation is irreversible and therefore needs to be highly accurate and tightly coordinated with mitotic exit. We combine perturbation experiments, live cell imaging and computational modeling to understand how this high degree of coordination is achieved. We want to find general principles that allow cells to execute highly dynamic processes with great accuracy. 


Funding

We are grateful for funding by the NIHNSF, and Virginia Tech!

Collaborators

Stefan Legewie, Alex Anyaegbunam  /  IMB, Mainz, Germany  /  computational modeling  /  regulation of anaphase

Andrea Ciliberto  /  IFOM, Milan, Italy  /  computational modeling / spindle assembly checkpoint

Jing Chen / Systems Biology, Virginia Tech / computational modeling / gene expression

Lenwood S. Heath  /  Department of Computer Science, Virginia Tech  /  bioinformatics  /  spindle assembly checkpoint

Past collaborators

Nicole Radde, Eva-Maria Geissen  /  University of Stuttgart, Germany  /  computational modeling  /  spindle assembly checkpoint

Jan Hasenauer  /  Helmholtz Zentrum Muenchen, Germany  /  stochastic modeling and statistics  /  spindle assembly checkpoint

Boris Macek, Karsten Krug, Alejandro Carpy  /  Proteome Center, University of Tuebingen, Germany  /  mass spectrometry  /  proteome and phosphoproteome across the cell cycle

Michael Knop, Susanne Trautmann  /  EMBL and ZMBH Heidelberg  /  fluorescence correlation spectroscopy

Gunnar Raetsch, Chris Widmer, Philipp Drewe  /  Memorial Sloan-Kettering Cancer Center  /  image recognition

Daniel Rauh  /  Chemical Genomics Centre of the Max Planck Society and Technical University Dortmund  /  chemistry  /  analog-sensitive kinases