CELL COMPETITION
As evolution guided the development of multicellular animals by uniting unicellular organisms, single cells have adapted their social interactions to engage in mainly co-operative relationships with their neighbours. Nevertheless, remnants of natural selection have remained an innate component of cell-cell interactions. Competition causes selection against relatively weaker cells, where a cell's fitness determines its competition potential. These "loser" cells are eliminated when in co-culture with stronger "winner" cells but are fully viable when grown separately. Indeed, Darwin's theory of the "survival of the fittest" applies at the cellular level. The Shakiba Lab seeks to uncover (reverse engineer) and program (forward engineer) the genetic rules of cell fitness in order to answer fundamental biological questions about stem cells and give rise to a novel class of engineered cell therapies for regenerative medicine applications.
OUR APPROACH
To uncover the genetic basis of cell competition, our lab uses genetic engineering techniques to perturb the gene fitness profile of cells, quantitatively tracking the dynamics of the cell populations using cellular barcoding technology. By using mathematical models to deconvolve the large datasets that emerge from these experimental studies, we are able to identify elite competitors. Finally, through the design of synthetic genetic circuits, whose designs are guided by control systems theory principles such as feedback/feedforward motifs, we are able to dynamically tune fitness genes, thus predictably controlling competition in multicellular populations.
TOOLS & EXPERTISE
LINEAGE
TRACING
We develop and utilize DNA-based cellular barcoding technology to track the dynamics of cells and their progeny within multicellular systems.
LIVE
IMAGING
We use live imaging to watch competition as it unfolds, relating the cell-intrinsic (genetic) fitness profile of cells with cell-extrinsic factors: their microenvironment.
COMPUTATIONAL
MODELING
We develop mathematical models to quantitatively analyze the sequencing datasets we generate, predicting the existence of elite competitor cells.
GENETIC
CIRCUITS
We use a modular cloning pipeline to develop synthetic genetic circuits to forward-engineer cell behaviour.
RESEARCH PROJECTS
What are the core genes that confer cell fitness? And are these genes orthogonal to the genes that encode cell type and lineage identity? Are some cell types inherently more fit than others and can differences in cell fitness play a role in how these cells emerge during development? Can fitness genes be tuned in cell types without changing their identity? These are the questions that motivate our lab as we seek to uncover and control the gene regulatory network of cell fitness in stem cells and their derivatives.