Research
In the System Immunology lab we study how the immune system utilizes specific context across the molecular and cellular scales to robustly respond to disease. The lab has three main focuses:
(1) Sequence level analysis of whole immune repertoires in health and in response to disease. The immune system generates a huge (1011) array of receptors. These function in tandem to defeat disease and block secondary infection. We are attempting to create a sequence level metric for whole repertoire diversity to study how the immune repertoire changes and deals with disease.
(2) Analysis of temporal processes related to the single cell level of the immune response. This includes the development of methods to analyze time courses of gene arrays and the analysis of Ca2+ dynamics in activated immune cells.
(3) Modeling of complex biological systems. -- we are widening our scope beyond the confines of immunology and utilizing some of the principles we have learned from the immune system to look at other complex multi scale biological systems. Mostly we are designing novel methodologies to study microbial biomes in urban settings (hospitals and daycares).
We are focusing at present on the following projects:
(1) How is a repertoire different than the sum of its parts : The B cell repertoire in health and disease:
Thanks to the diversity of the B cell repertoire the immune system can adapt to nearly any pathogen it encounters. This ability protects from recurrent infections, helps guard against rapidly mutating pathogens and is the basis for vaccines. Despite its importance the nature of this diversity and how it is generated remains unknown. The evolution of multivariate receptor repertoires and the selection of specific subsets, during the lifetime of the organism, cannot be understood at the level of a single cell. We study this system by developing tools that allow us to analyze and visualize nucleotide and protein relationships at the level of the whole repertoire of cells. Using these tools we are starting to identify how the B cell repertoire retains homeostasis while maintaining focus on specific epitopes.
Collaborators: Eline Luning Prak, Michael Cancro, and Yair Argon (UPenn), Peter Katsikis and Brian Wigdahl (Drexel Med), Steven Kleinstein (Yale), Mark Shlomchik (UPitt), Yoram Louzoun and Sol Efroni (Bar Ilan); Debora Dunn-Walters (Imperial), Ali Shoukoufandeh (Drexel), Santiago Ontañon
Students: Gregory Schwartz -- Analysis of short amino acid motifs and of patterns of variability and stability at the amino acid level in Immune receptor sequences, across the resting immune repertoire and following influenza infection and vaccination; Jasmine Saini -- How can biased codon usage influence the tendency to change upon mutation in immune repertoires?; Bochao Zhang -- The creation of a precise metric to assess the accuracy of germline association in Immune cells; clonal association and overlap between sub
(2) Time course analysis of molecular processes (Transcription and signaling)
Despite their central importance, the basic architecture and temporal dependencies underlying most eukaryotic gene programs are poorly understood. Such an understanding is essential if we wish to explain how cells integrate multiple stimuli using a limited vocabulary of signaling molecules, to create a vast multiplicity of behaviors. Using time-explicit models of regulatory cascades, we can start to define regulatory events underlying specific decision-points in cells undergoing short-term differentiation. In the lab we use such tools to study dendritic cell (DC) differentiation in the antiviral response. Identifying for the first time the precise timing leading to a functioning anti-viral response. Another avenue in which we are brining more dynamical models to the study of intracellular signaling in immune cells is in the study of Ca2+ flux. Ca2+ flux and action potentials have been known for some time to be a major signaling factor in neurons. Where they are tightly linked to learning and neuronal development. Only recently have imaging methods matured allowing us to study how the fluctuations and control of Ca2+ relate to the internal signaling of activated immune cells. We are developing methods to analyze this data and create models of the temporal control of Ca2+ in immunity.
Collaborators: Steven Kleinstein (Yale); David Allman and Bruce Freedman (U Penn)
Students: Justin Melunis and Corbett Berry -- Analyzing the Ca2+ flux in activated and resting immune cells
(3) Modeling of complex biological systems:
One of the major themes of our research into biological systems in general and immunology in particular is that these systems are by their very nature multi-scale. We propose that to understand biological control we must create an analysis which links between scales. These models must combine the underlying level where interactions occur (the microscopic scale) and the higher level where behaviors are found to emerge (the macroscopic scale). During my time at Drexel I have managed to expand my interests beyond immunology and use both the methods and sensibilities I have developed studying immunity to study other complex biological systems. These ongoing researches include: (i) Modeling and comparing patterns of cell motility and directed movement from 2D and 3D imaging experiments. (ii) Creating explicit 4D models (3D maps updated over time) of bacterial biomes and spread in urban environments. (iii) Codon usage, nucleotide distribution and the detection of selection in the genome (outside of immune genes) and in viral species competition. (iv) Developing a general model for the role of Complexity in the development and evolution of living systems.
Collaborators: Andrew Cohen, Gail Rosen, Nicole Koltick, Yasha Kresh, and Brian Wigdahl (Drexel); Ruth Hershberg (Technion); Theodore Muth (Brooklyn College); Lev Muchnik (Hebrew University); Gur Yaari and Yoram Louzoun (Bar Ilan); Murat Elibol (Ege)
Students: Justin Melunis -- simulation tools for the comparison of directionality and other cell and organelle movement patterns, as derived from cell imaging analysis over time. Erin Reichenberger - GC codon usage in viral and microbial species from related environments as an indicator of common functional background. Jasmin Saini -- What drives the patterns of GC / CG and TA / AT dimer usage in coding and non-coding regions in the mammalian genome? Does the codon usage of immune receptor genes follow these patterns? Mesut Yücel - Modeling robust signaling pathways as an emergent phenomena of the dynamics of competing signaling cascades. Laurie Barnwell -- Creating a GIS like system to describe the spread of microbial pathogens in a hospital. Gregory Antell: Do HIV subsets in neural tissue, beyond the blood brain barrier, experience lesser amounts of selection pressure from the immune system? Can this be seen in following the patterns of mutation they undergo?