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Graduate Program: Research Areas
Concentration in Developmental Biology
This burgeoning field of biology seeks to understand how complex tissues and organisms arise from the ordered expression of genes and signaling interactions between cells. It employs modern molecular biology approaches, combined with cell biology and physiology techniques, to probe some of the most fundamental questions in biology. Our laboratories use a variety of vertebrate and invertebrate model systems to examine developmental events at different times in the formation of an organism.
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Associated faculty mentors not currently accepting graduate students: Dany Adams, Susan Ernst, Juliet Fuhrman
The building of organs during embryogenesis constitutes one of the most fascinating, but also least understood developmental processes. Coordinated gene action directs the developmental fate of cells to assemble into complex, three-dimensional structures with characteristic shape, size, and physiological properties. The acquisition of different cell fates initiates an elaborate interplay of cell proliferation, migration, growth, differentiation and death, bringing together cellular ensembles in a precise temporal and spatial manner. The mechanisms which intrinsic and extrinsic factors use to generate cell diversity, coordinate morphogenetic cell movements, and regulate assembly of the different tissue types comprising an organ, define one of the central questions in science today. Our research seeks to discover the basic mechanisms of vertebrate organ development, repair, and regeneration. Recent advances in Developmental Biology hold great promise in many areas of human adult and child health where the discoveries of today develop into the treatments of tomorrow.
Research Summary: The primary objective of our research is to understand how functional organs are created. Although many of the mysteries of biology have been revealed over the years, the precise molecular mechanisms used by organisms to create and pattern tissues and organs remain a mystery. Our lab takes advantage of the powerful molecular developmental model system, Xenopus laevis (frog) and uses multiple approaches in order to gain a better understanding of how organs are formed including: 1) normal organ developmental processes, 2) organ remodeling, and 3) regeneration.
The capacity to generate a complex organism from the single cell of a fertilized egg is one of the most amazing qualities of multicellular animals. The processes involved in laying out a basic body plan and defining the structures that will ultimately be formed depend upon a constant flow of information between cells and tissues. The Levin laboratory studies the molecular mechanisms cells use to communicate with one another in the 4-dimensional dynamical system known as the developing embryo, and the flow of information necessary for an injured system to recognize what structures must be rebuilt. Through experimental approaches and mathematical modeling, we examine the processes governing large-scale pattern formation and biological information storage during animal embryogenesis and regeneration. Our investigations are directed toward understanding the mechanisms of signaling between cells and tissues that allows a biological system to reliably generate and maintain a complex morphology. We study these processes in the context of embryonic development and regeneration, with a particular focus on the biophysics of cell behavior. In contrast to other groups focusing on gene expression networks and biochemical signaling factors, we are pursuing, at a molecular level, the roles of endogenous voltages, pH gradients, and ion fluxes as epigenetic carriers of morphological information. Using gain- and loss-of-function techniques to specifically modulate cells' ion flow we have the ability to regulate large-scale morphogenetic events relevant to limb formation, eye induction, etc. While our focus is on the fundamental mechanisms of pattern regulation, this information will also result in important clinical advances through harnessing the biophysical controls of cell behavior.
DNA double-strand breaks are a double-edged sword for cells. They can enhance genomic plasticity and are important for developmental processes such as immune system development. However, they can also promote genomic instability and lead to diseases such as cancer. These breaks can be repaired by two main classes of mechanisms: non-homologous end-joining and homologous recombination. End-joining entails processing of broken ends and subsequent ligation and is often error-prone (it can be thought of as the "duct tape" approach to repair). Homologous recombination involves using a homologous template for repair. While it has been traditionally thought to be error-free, we and others have evidence that it can be mutagenic.
Different cell types employ these double-strand break repair mechanisms (or combinations of them) to different extents during development, depending on cell cycle and developmental cues. Our laboratory is using Drosophila melanogaster as a model system to investigate how and when these mechanisms are used in different cell types and to characterize genes that play crucial roles in each pathway. Our research employs a variety of classical and molecular genetic approaches, including powerful assays in which we can create double-strand breaks at known sites in the genome and recover and molecularly analyze repair events. Our long-term goal is to elucidate the mechanisms by which cells "choose" the appropriate pathways to repair different types of DNA breaks.
During embryogenesis, a developmental program encoded in the genome is expressed to create a three-dimensional organism. My students and I are interested in the molecules and mechanisms that direct and regulate this process. We have concentrated on questions of very early development and cell differentiation and how the early cell lineages become established. Using sea urchin gastrulation as a model system, we study genes that code for proteins thought to be instrumental in the morphogenetic processes required to change an undifferentiated ball of cells to a gastrula with three primary germ layers, from which all the cells and organs of the embryo will arise. Endo16, a gene that is the focus of many of our current studies, encodes a protein that appears on the surface of the invaginating archenteron cells just as they initiate the dramatic morphogenetic movements of gastrulation.
Our laboratory is currently studying the basic biology of parasitic roundworms in the hope of devising novel strategies for controlling infection and preventing disease. We focus in particular on filarial parasites, which are responsible for causing elephantiasis and onchocerciasis, or river blindness, in humans. Filarial parasites currently infect nearly 100 million people, most of whom live in developing nations that cannot supply expensive drug cures or implement costly control plans. We have recently used a combination of immunochemical and molecular approaches to define a "virulence factor" in Brugia malayi; this factor, the enzyme chitinase, is apparently required for the parasite to develop within the mosquito. We are studying the enzyme chitinase's structure and enzymatic properties as well as its localization within the parasite. Its precise role in the mosquito is being tested using inhibitors and recombinant protein, and its developmental regulation is being examined through genomic and cDNA analyses. The laboratory is also investigating other aspects of the mosquito-parasite interaction through an analysis of specific components of the mosquito gut that determine the insect's susceptibility to infection.
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