Patterns of biological damage: managing subsystem failure in cellular systems

  • Rutenberg, Andrew (PI)

Project: Research project

Project Details

Description

Biological systems eventually fail, rupture, break, or die. These systems actively avoid, repair, and manage subsystem failure during self-organized growth and development. My group will computationally model biological failure at different levels of organization from the molecular to the organism. We want to understand how living systems control spatial and temporal patterns of damage and failure, and to learn from living systems how to design and manipulate useful and resilient response to failure at the nanoscale. We will study failure across scales, from subsystem to system. For example, how molecular failure affects macromolecular mechanisms, or how organelle failure affects cellular function. We will use the theoretical tools of soft-materials, statistical, computational, and biological physics to focus on physical aspects of failure. We will pursue three directions at distinct levels of organization: collagen tissue, peroxisome number and quality control, and bacterial invasion of host cells.Type-I collagen is important for connective tissue. It is built by tropo-collagen molecules assembling into fibrils. We will develop an elastic model of collagen fibrils with both discrete fibril damage and rupture of loaded bundles of fibrils. We will also explore the energetics of tropo-collagen alignment within collagen fibrils, in order to understand when damage becomes energetically favourable. Together, we will be able to predict collagen materials properties from laboratory measurements of individual fibrils. This would allow us to efficiently explore the molecular determinants of collagen damage and failure.Peroxisomes are small metabolically-active essential organelles within cells. Unneeded and damaged peroxisomes are selectively removed by the cell through a process called autophagy. Very little is known about peroxisome damage processes, and in particular how peroxisome function is maintained by the cell in the face of continual damage. This will be the focus of our modelling. The result of our work will be to better understand how cells dynamically manage large numbers of small organelles.The invasion of a host eukaryotic cell by a bacterium involves a variety of levels: the host tissue, cells, and subcellular compartments and processes but also the removal of individual bacteria by autophagy. Cellular infective process involve cellular invasion, escape into the cytoplasm, reproduction, and transmission to adjoining cells. We will model interactions between different bacteria, and between different stages of infection in these systems. These will be complemented by more mechanistic models of the different stages of invasion. As our programmes in peroxisomes and bacterial invasion mature, they will be combined to lead to additional insight into the mechanisms of dynamic regulation of number and function of small organelles or bacteria in host cells.Progress will be accelerated with active experimental collaborations in each direction. This will let us bring interesting problems from biology into physics. We will also make physics techniques useful for biologists by connecting quantitative modelling with data driven experiments. These will help us to develop a multi-level understanding of these biological systems, by combining biological, biophysical, and modelling approaches. This will highlight physical mechanisms of cause and effect in these systems. Identifying and understanding the mechanisms behind robustly quantitative phenomenology will allow us to turn each phenomenon, and its associated phenotypes, around into tools to look deeper into how biological systems work in the face of damage.

StatusActive
Effective start/end date1/1/17 → …

Funding

  • Natural Sciences and Engineering Research Council of Canada: US$19,254.00

ASJC Scopus Subject Areas

  • Biophysics
  • Medicine (miscellaneous)
  • Physics and Astronomy (miscellaneous)