Award details

SysMO LAB (Hugenholtz)-Westerhoff

Reference	BB/F003552/1
Principal Investigator / Supervisor	Professor Hans Westerhoff
Co-Investigators / Co-Supervisors	Dr Frans Bruggeman, Professor Jacob Snoep
Institution	The University of Manchester
Department	Chem Eng and Analytical Science
Funding type	Research
Value (£)	267,624
Status	Completed
Type	Research Grant
Start date	01/10/2007
End date	30/09/2010
Duration	36 months

Abstract

Challenge: The central principle of this proposal is that important aspects of the functional differences between organisms derive from the interactions between their components. This project will develop Comparative Systems Biology (CSB). Model system: The project focuses on three relatively simple and highly related microorganisms, which nevertheless exhibit stark and important differences in their functional relationship with human beings: These homofermentative lactic acid bacteria are Lactococcus lactis, the major microorganism used in the dairy industry, Enterococcus faecalis, a major (fecal) contaminant in food and water as well as a contributor to food fermentation, and Streptococcus pyogenes, an important human pathogen. These organisms have similar primary metabolism, but persist in completely different environments (milk, faeces, blood). Lactococcus lactis will be used as the reference microorganism, since: (i) it is by far the best studied lactic acid bacterium, (ii) three different genomes have been sequenced, (iii) a kinetic model has been developed for its complete glycolysis including some branching pathways, (iv) genetic and metabolic engineering tools are available and (v) a functional genomics platform has been set-up including DNA microarray and metabolic databases. Methodology: The project will focus on carbon metabolism and its response to aeration, change of sugar-source, addition of heme and elimination of the crucial metabolic enzyme, lactate dehydrogenase. Cells will be grown in a non-nutrient-limited turbidostat that will allow maximal growth under defined conditions. The major regulatory events at the genetic level (adaptive mutations), the transcription, translation, enzymatic and metabolic level up to the final output (functional) level, will be quantified and then integrated in iterations between experimentation (all~omics) and modeling (network structure, flux balances, dynamics, control, regulation).

Summary

Molecular and genomics approaches have contributed greatly to our understanding of bacteria. They have also led to a number of surprises. One is the fact that organisms that appear to be highly different are rather similar in terms of their molecules. Many of the molecular components of humans are similar to components of bacteria. Even closer similarities have been found between bacteria that are highly different in the way they interact with human beings. A recent development in the sciences, called Systems Biology, recognizes that the functioning of living organisms is not merely determined by their components, but also by properties that emerge from the interactions between those components, just like the scoring by a football player is not just determined by that player himself. Here we propose to test our hypothesis that much of the differences between organisms derives from differences in the interactions between their components. Three related organisms will be compared, one that produces our cheese, one that is a fecal contaminant of food, and one that causes sore throats. The networks of the three bacteria will be unraveled, the flow of carbon and energy through those networks will be determined, and the extent to which the bacteria are able to adjust their networks to altered environments will be measured. The results will be assembled into computer models that should then reproduce the behavior of the bacteria. It will be examined whether and how these computer versions of the organisms explain the differences in the extent to which they cause disease or function as organisms that help produce our food. These explanations will then be tested experimentally.

Committee	Closed Committee - Plant & Microbial Sciences (PMS)
Research Topics	Microbial Food Safety, Microbiology, Systems Biology
Research Priority	X – Research Priority information not available
Research Initiative	Systems Biology of Microorganisms (SysMo) [2007-2008]
Funding Scheme	X – not Funded via a specific Funding Scheme

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