Summary of research interests
Multicellular organisms have evolved a great variety of cell types that perform specialized functions. Stem cell progeny that are destined to differentiate proliferate transiently and choose one of those cell types. This differentiation process, of great spatial and temporal precision, is at the heart of development and organ homeostasis. How differentiation is controlled is thus a question of tremendous importance from scientific and therapeutic standpoints. Although much progress has been made over the last century, a major stumbling block has appeared in the form of the complexity of the regulatory networks controlling differentiation. One finds that the gene-based approach that has served 20th-century biology so well is reaching its limits: we now need to understand the staggeringly-complex set of interactions between genes that have already been identified, rather than continue an endless pursuit of new genes.
We follow three complementary approaches to address the regulation of cell proliferation and differentiation. In a first approach, we start from a fecund, simple model organ whose regulation has been extensively characterized at the genetic and biochemical levels: the C. elegans germ line. We ask how the current knowledge of regulatory parts all fits together to explain organ-level behavior. We perform experiments that target organ-level behavior of the germ line, rather than individual genes in the regulatory network. Guided by these experiments, and building on knowledge generated by many labs over the past 30 years, we use mathematical and computational methods to analyze how the regulatory network accounts for organ-level control of cell proliferation and differentiation.
In a second approach, we start from noteworthy regulatory modules that appear in a variety of differentiation “switches” across species. We ask what interesting behaviors of those modules are, what new insights these behaviors might provide on system-level function, and whether they shed new light on previous experimental data.
Finally, since nothing in biology makes sense except in the light of evolution, we will ask theoretically and experimentally how evolution shapes regulatory networks controlling cell differentiation.
Recurrent players in our research are the Notch and FGF/MAPK signaling pathways and bHLH proteins, and important concepts are positional information and developmental timers and clocks. These are relevant to countless developmental and medical questions. We are also interested in more direct implications of our research for the fights against helminths (a major burden for developing countries that could worsen as drug resistance develops) and against metabolic diseases.
Prospective students and postdocs
The lab will be progressively developing projects in the following areas (email me for more specifics).
- imaging of gene expression in live and fixed C. elegans germ lines (with classical confocal microscopy and FCS), experimental manipulation of the C. elegans germ line
- synthesis of model differentiation switches
Image processing: segmentation and quantification of expression patterns
Software: development of organ-centric, online collaborative databases with advanced visualization features
Modelling: mathematical and computational investigation of model regulatory networks