Division of Immune Diversity

Unlike most other cell types in the body, which are static, immune cells must travel through (and adapt to) multiple different environments on a constant basis. This ability to adapt is predicated on molecular mechanisms that generate informational diversity, such that every immune cell is genetically different that every other (which is the case with cells of the adaptive immune system, such as B and T lymphocytes) or transcriptomically different than their siblings (which appears to be the case with inmate immune cells, such as cells of the monocytic lineage). Overall, the goal of our research is to understand the molecular processes that generate phenotypic diversity, which in turn is required for adaptation.
This interest originally directed my lab's work to DNA diversification in the context of the adaptive immune response, specifically to mechanisms that direct DNA mutation to antibody genes in the germinal center. This process, which depends on AID-mediated DNA deamination followed by error prone repair, generates immunoglobulin sequence diversity and underlies affinity maturation of the antibody response.
More recently, my lab has begun studying population diversity in the context of the innate immune response, as it is generated by rampant but targeted RNA editing (an "active" form of mutation, which depends on expression of the editing deaminases APOBEC1 or ADAR, and which unlike DNA mutation does not leave a mark on the genome). For these studies we developed new tools that took advantage of next generation sequencing to generate custom bioinformatic approaches within the lab, as well as mathematical modeling to deconvolute RNA editing as it occurs in single cells, to generate heterogeneous populations with an increased capacity to adapt to changes in the environment.
Finally, we have an active interest in the regulation of coat protein diversification in parasites (specifically, the African trypanosome T.brucei), which appears to be mechanistically similar to Ig diversification. To answer long-standing questions in this field, we have taken advantage of our work in immunology and bioinformatics, to (1) import new tools to study the initiation of VSG diversification in vitro and to (2) generate new approaches to study VSG diversity at the population level in vivo both in terms of sequence diversity and in terms of antigenic plurality. Overall, this aspect of our work should provide a robust (and generalizable) mechanistic understanding of a changing antibody response toward an antigenic coat that changes just as rapidly, and their co-evolution through time.

We are very interested in understanding the role of DNA mutation and RNA editing in the generation of proper immune repertoires; and are also keen on understanding how these mechanisms, that have evolved to generate immune diversity, are co-opted in the context of tumours to help them evolve resistance. We are interested in understanding relapse from a clinical perspective, as well as through in vitro proof-of-principle studies.