A fundamental feature of animal cells is their ability to differentiate for the purposes of specialized function. This sometimes but not always is accompanied by arrested proliferation. However, differentiation is irreversible; once a cell has differentiated, it does not go back, with the exception of some cancers. Essentially, the problem of differentiation is an informational one. How is the cell informed to differentiate; how does it interpret that information; how does it remember to stay in the differentiated state.
We use the model experimental system of Drosophila to answer these questions. We use a variety of quantitative methods in our experiments, including real-time imaging of differentiating tissues, single-molecule FISH, and use of fluorescent protein tagging coupled with quantitative microscopy to measure protein levels in individual cells within tissues. We work closely with theorists in applied mathematics and engineering to construct models that explain and predict our experimental data.
We employ systems-level analysis to the problem, reasoning that the ways in which cells differentiate rely on mechanisms that are sometimes counter-intuitive. Systems biology is able to discover mechanisms that do not make intuitive sense, yet nevertheless exist. For example, we have found that cells exploit the fact that gene expression is inherently noisy in order to jump the barrier between the undifferentiated and differentiated states. This is akin to proteins relying on random thermal fluctuations in order to fold into a stable conformational state. Another example is that cells will switch states not dependent on the absolute concentration of regulatory proteins but on the relative molar ratio of regulatory proteins.
Some of the questions we are pursuing have to with the following. How do cells capitalize on gene expression noise. How do cells decode a relative molar ratio into permanent changes in gene programming. How do ubiquitous signals between neighboring cells provide specific information. How does cell geometry and the tensions felt by cells control their differentiation.