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17 december 2018

Approved FOM programme

Number 161.
Title The signal is the noise: seeking physical origins of fluctuations in organism-scale (NOISE)
Executive organisational unit AMOLF & BUW
Programme management Dr. T.S. Shimizu
Duration 2015-2020
Cost estimate M€ 2.5

The objectives
We seek the principles and physical mechanisms of biological stochasticity to answer a fundamental question: why is organism-scale behavior so variable? We will measure fluctuations at multiple scales in the motile behavior of the nematode C. elegans – from single molecules to the whole organism – and develop new theoretical frameworks to bridge scales.

Background, relevance and implementation
Whereas biological 'noise' at the molecular and cellular level has received much attention of physicists in the past decade, sources of randomness in the behavior of complex multicellular organisms have scarcely been explored. For example, is such variability the result of molecular fluctuations transmitted to higher levels? Or is it injected directly by the dynamics of genetic, neural or other biophysical networks? We identify motile behavior of the nematode C. elegans as an ideal biophysical arena to address this question, and propose a research programme to measure fluctuations arising at multiple scales – from molecules to cells to the organism as a whole – and develop new theoretical and computational frameworks that will help understand how these diverse sources of noise are generated, and how they might affect the functioning of biological systems at the organism level.

In this programme, we leverage the advantages of the C. elegans model system to seek the physical origins of behavioral variability at three levels of biological organization, with the analysis at each level driven by a central research question: (1) What is the structure of behavioral fluctuations across multiple timescales, and can we identify sources of variability at the level of neurons? (2) Can we identify specific genes that are the 'prime movers' of behavioral variability, quantify the noise in their expression levels, and understand how this noise is regulated? and (3) How are additional fluctuations generated at the cellular level by gene products (i.e. protein molecules), and can such cellular variability be propagated up to organism-scale behavior?

Each of these three research questions are embedded in a workpackage (WP), in which two to three PI groups work collaboratively to address variability at three scales: behavioural and neural dynamics (WP1), gene-expression noise (WP2), and cellular noise (WP3). In addition, two 'synergy cores' (SC's) will provide essential technical expertise for the programme as a whole: the first (SC1, Biological physics) leads the development of theoretical and computational frameworks to connect the diverse data sets; the second (SC2, C. elegans technologies) provides crucial technical support and services required for in vivo biophysical experiments, via an array of state-of-the-art genetic and cell-biological techniques.

The final evaluation will be based on the self-evaluation report initiated by the programme leader and is foreseen for 2020.