Doubrovinski Lab
We study the physical mechanisms that underlie animal development.
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More specifically...
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A major focus of our research is Drosophila melanogaster (fruit fly) gastrulation. Any animal starts off as a single ball of epithelial cells called a blastula. Subsequently, a subset of cells located on one side of the blastula shrink at one end, concomitantly elongating about twofold. Finally, the constricted cells form a fold on the surface of the embryo and disappear into the embryonic interior. This process is called gastrulation. The reasons to study gastrulation are two-fold. 1). Gastrulation is conserved across all metazoans: any self-respecting animal from sponge to human undergoes some variant of gastrulation. 2). Gastrulation is closely related molecularly, cell biologically and, in all likelihood, mechanistically to a wide range of morphogenetic events in many different animal models at many stages of development.
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Despite many decades of research, the physical mechanisms that underlie gastrulation are largely unknown. Based on general considerations from continuum mechanics, we believe that a meaningful model of any morphogenetic event requires two pieces of information. 1). The knowledge of forces that drive tissue deformation. 2). The knowledge of material properties of the embryonic tissue that is being deformed. To directly measure mechanical properties of embryonic tissues we employ rheological measurements. Specifically, we subject tissues to controlled forces and study their resulting deformations. To study active forces involved in driving gastrulation, we use a combination of imaging, opto-genetics, and FRET-based molecular stress sensors. We believe that the combination of these experimental approaches, together with theoretical modeling, has the potential to ultimately determine the underlying physical mechanism uniquely.
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More broadly...
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The main concepts behind what we do are scale and emergence.
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Scale.
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An animal cell has a size, typically between 10 and 100 microns. What maintains that particular size? Cells can crawl on surfaces with some (average) speed. What sets the speed? Cells have some specific number of inner organelles. Why that number? These are examples of questions asking how a certain scale (some dimensional quantity) characterizing a cell arises at a molecular level. It is self-evident that these questions are amongst the most fundamental to biology. Yet, the above, as well as many other similar questions remain unanswered.
Our lab seeks to understand scales that are relevant to animal development. In the course of development, many (if not most) animal organs form from folds of epithelial tissue (primordia). The structure and dynamics of organ primordia may be characterized by a number of physical scales such as their characteristic sizes, the times required to attain their respective final shapes and the magnitudes of forces that drive their formation. These are the type of questions our lab seeks to address.
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Emergence.
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A fly larva is approximately 500 microns long when it hatches. There are means to make a larva significantly shorter. Remarkably, shorter larvae have heads that are proportionately shorter; i.e. the ratio of the size of a larva’s head to the length of its body is the same regardless the size of the larva. We (probably) know all genes involved in achieving this remarkable scaling. We have a somewhat detailed knowledge of how these genes interact with one another. However, the scaling is not yet understood: we do not have a predictive and quantitative model that explains how the size of the head is tied to the size of the body. This is one example of emergence: the behavior of the whole network is more than the sum of individual gene-gene interactions.
Another example of emergence can be seen in the dynamics of tissue deformation. During animal development, cells interact mechanically: forces generated by a given cell are transmitted to its neighbors. However, those neighbors have neighbors too. In this way, mechanical deformations that accompany animal development are collective phenomena: understanding the dynamics of a given cell requires considering interactions of all cells in the tissue. In both cases above (genetic networks and tissue mechanics) the interactions among individual components can not be tracked mentally, mathematical modeling is absolutely necessary for understanding emergent properties. Our lab is working to develop such mathematical models.
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