DEPT. OF DEVELOPMENTAL AND CELL BIOLOGY
My lab is interested in the control of cellular behaviors, with the word control being used in its engineering sense: the deliberate execution of strategies for achieving useful ends, such as precision, robustness, efficiency and fast response, etc. The processes of development and regeneration provide impressive examples of tight control of growth, differentiation and patterning. Numerous developmental processes have been extensively studied from a mechanistic perspective (What happens? What molecules are involved? How do they work?), but only recently have serious efforts been directed toward understanding the logic of control (Why is the system configured the way it is? What purpose does it serve?). We seek to address such questions in the context of several mechanistically well-understood problems in pattern formation, growth regulation and regeneration.
Because control problems are systems-level problems, i.e. they deal with the behavior of an entire system in its environment, we utilize many of the tools of the emerging field of Systems Biology in our research, including mathematical modeling, computational simulation, large-scale data collection, and high-resolution live cell imaging. To facilitate this work, we collaborate extensively with mathematicians, computer scientists, physicists and engineers.
Several of the projects in the lab deal with morphogen gradients and their role in pattern formation. Morphogens are diffusible molecules that are released at one location in a tissue and by virtue of transport (e.g. diffusion) create spatial gradients to which surrounding cells respond differentially, according to the morphogen concentration they measure. It is now well established that many cells in developing organisms receive their positional information, which enables them to grow or differentiate appropriately for their locations, from morphogen gradients. How the mechanisms that create such gradients achieve the right levels of morphogen at the requisite points in space, despite the presence of large intrinsic and environmental disturbances, is still a mystery. We believe that a great deal of the molecular machinery utilized in the formation of morphogen gradients exists because it is needed to counteract or filter out such disturbances. We already have many clues about different ways in which individual classes of perturbations may be resisted, but mathematical modeling (and the real world experience of engineers) tells us that strategies designed for single purposes often interfere with each other. The need to be robust to many types of disturbances drives engineered systems to become quite complex, and we have every reason to believe the same is true for biology. Put in other words, there is every reason to believe that the much of the complexity of biology only makes sense in the context of its role in control.
Our theoretical work on morphogen gradients has led us to carry out experimental studies on mechanisms of co-reception and mechanisms of morphogen transport. Co-reception refers to the phenomenon whereby cell-surface molecules other than morphogen receptors interact either with morphogens or their receptors to modulate the gain of morphogen signaling. Our work on heparan sulfate proteoglycans suggests that these widely-used co-receptors accelerate the assembly of cell-surface signaling complexes for bone morphogenetic proteins (BMPs), one of the major classes of morphogen. Our work on morphogen transport has focused primarily on visualizing BMP transport within the living fruit fly wing disc (a larval tissue that is patterned by a BMP gradient), using such techniques as fluorescence correlation spectroscopy and photo-activation of fluorescent fusion proteins. We also study the roles of the morphogen retinoic acid in the zebrafish embryo, and fibroblast growth factors (FGFs) in the developing mouse forebrain.
Whereas biological patterning requires achieving the right concentrations of diffusible molecules at specific locations in space, development also requires that tissues generate the right numbers and types of cells in the right interval of time. We have focused on the ways in which extracellular feedback, through secreted molecules, is used within tissues to achieve robust control of size and cellular composition. Our work on the mammalian olfactory epithelium suggests that a complex set of negative and positive feedback loops, acting within distinct lineages, is needed to balance competing demands for fast, accurate, and stable tissue development. This work has provided new insights into why cell lineages exist, what stem cells really are, and how regeneration is orchestrated.
This work has also enabled us to better understand how mutations lead to changes in body and organ size. One such mutation we study is in the mouse Glypican-1 (Gpc1) gene which, when mutated, leads to a marked reduction in brain size. Our recent work implies that Gpc1 regulates the gain of an FGF-mediated, positive feedback loop that controls that probability that progeny of neural progenitors remain undifferentiated.
Not only does feedback control of lineage progression play important roles in tissue and organ development, we believe it also has a major impact on the formation and growth of tumors. Indeed, the recent realization that Cancer Stem Cells drive the growth of many cancers is really just an acknowledgement of the fact that lineage progression continues to operate even after cells have become transformed. A variety of observations suggest that, not only lineages, but the feedback controls that exist within them, continue to exist in tumors (albeit with altered parameters). We have begun a collaboration, funded by a Grand Opportunities Grant from the National Cancer Institute, with mathematicians, computer scientists, evolutionary biologists, and cancer biologists to use modeling and machine learning to discover the signatures of different forms of lineage feedback control in the three-dimensonal spatiotemporal trajectories of growing tumors.
A final area of study within the lab deals with a relatively common, severe birth defects syndrome, Cornelia de Lange Syndrome (CdLS), which is caused by a small reduction in the level of the produce of the NIPBL gene. NIPBL regulates cohesin, a structural component of chromosomes, and appears to influence long-range cis-regulatory interactions throughout the genome. We developed a mouse model with which to understand the pathophysiology of CdLS, and to develop new diagnostic and therapeutic modalities. Analysis of this model implies that small changes in the expression of a large number of genes collectively give rise to the birth defects observed in CdLS. Thus, CdLS appears to be a single-gene disorder with an etiology much like those of highly polygenic traits. We are actively working on the Systems Biology of CdLS, as a way to understand the rules governing the emergence of complex, polygenic phenotypes.
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