The Project
Investigate the causes and consequences of natural patterns of phenotypic variability, aging and death in cellular lineages.
Winner
François Taddei
INSERM University Paris 5 Medical School
U571 Medical and Evolutionary Molecular Genetics
Paris, France
www.necker.fr/tamara
Head of the interdisciplinary master for life sciences, Ecole Normale Supérieure, Paris 7 University, Frenchman François Taddei, 38 years old, obtained his Master's in Cellular and Molecular Genetics from the University of Paris VI and XI in 1991.He went on to obtain a Ph.D in Molecular Genetics in 1995 and his Habilitation à Diriger des Recherches in 1999, both from the University of Paris XI (Orsay). He has been published internationally in over 40 peer-reviewed journals and other publications (book chapters or didactic reviews).
Award
€1,199,196
Project Description
While the effect of genetic and environmental differences on the phenotypic(*) variability of populations have been explored thoroughly, the nature of the differences between single, isogenic cells in a constant, homogenous environment remains mostly uncharted territory. It is even uncertain which of these differences are of a stochastic versus a programmed epigenetic nature, partly because of past technical difficulties of working on individual cells and their descendents.
This project aims at understanding the causes of this phenotypic variability on the level of the single cell. To achieve these goals we have developed image acquisition and analysis tools, which we have combined with the genetics of Escherichia coli. Using these new tools we can follow the cell growth and division of a single cell through to 1,000 offspring stage, the genealogical relationships between these cells, and their physiological parameters (growth rate, length, etc). In addition, using fluorescent protein fusions, the level of gene expression and protein localization within the cell can be followed over many generations, allowing the investigation of the functional roles of proteins involved in cellular variability.
We have found that subsets of cells show phenotypes significantly different from that of the “average” cell; in some growth will slow down and even stop, phenomena which can be associated with the spontaneous over-expression of certain genes or with cellular aging. These results make it possible to plan to unravel the mechanisms involved in errors and variability in gene expression, protein aggregate dynamics, epigenetic and cytoplasmic inheritance, bacterial persistance despite antibiotics treatments, and cellular degeneracy. This work will bring new tools and concepts that could be adapted to eukaryotic (including human) cells where the causes and consequences of the natural patterns of phenotypic variability, aging and death in cellular lineages have not yet been addressed with such exhaustive and rigorous innovative approaches.
(*) Definition - Phenotype:
The phenotype of an individual organism is either its total physical appearance and constitution, or a specific manifestation of a trait, such as size or eye color, that varies between individuals. Phenotype is determined to some extent by genotype, or by the identity of the alleles that an individual carries at one or more positions on the chromosomes. Many phenotypes are determined by multiple genes and influenced by environmental factors. Thus, the identity of one or a few known alleles does not always enable prediction of the phenotype. Nevertheless, because phenotypes are much easier to observe than genotypes (it doesn’t take chemistry or sequencing to determine a person’s eye color), classical genetics uses phenotypes to deduce the functions of genes. Breeding experiments can then check these inferences. In this way, early geneticists were able to trace inheritance patterns without any knowledge whatsoever of molecular biology. (Source: Wikipedia)
