What sharks are teaching us about the evolution of adaptive immunity
Research in the Dooley Lab: I am an evolutionary immunologist interested in the development of new methods to understand, diagnose, and potentially treat, human and animal disease.
There are two main aspects to my work; the first is driven by a desire to understand how the components of the immune system emerged and have since evolved. To do this I use a comparative approach, examining a specific immune molecule or pathway in many different animal species and comparing them to look for shared properties and/or rules that govern their function. An essential part of this are our studies on the immune response of sharks and their close relatives the skates, rays, and chimera (all cartilaginous fishes); this group are especially important as they are the most ancient species to have a ‘human-like’ adaptive immune system (with polymorphic/polygenic MHC molecules and diverse repertoires of immunoglobulins and T cell receptors generated by somatic recombination). We have previously conducted long-term immunization studies in a number of species of shark and shown they can generate robust, antigen-specific antibody responses, despite lacking isotype switching and conventional germinal centres. We have now moved on to study the molecules involved in B cell development/maintenance and regulation of the adaptive response. As cartilaginous fish are still relatively understudied from a genomic perspective we use next-generation sequencing to generate high-coverage, multi-tissue transcriptomes, that can be searched for immune molecules of interest. Our recent findings suggest the molecules required for B cell maintenance may differ between fishes and other vertebrates and we are now investigating these molecules using techniques such as quantitative PCR, recombinant protein production, structural analysis, proteomics, as well as conductingfunctional studies in vitro/vivo.
The second aspect of my work is the development of new technologies/therapies to understand, diagnose, and potentially treat, human and animal disease. During our research we often come across novel molecules that sharks (and other species) use to detect infection and protect themselves from disease; with sufficient development, some of these molecules may provide the next-generation of diagnostic and therapeutic agents. A large part of my work to date has focussed upon the novel antibody isotype, IgNAR, which is only found in the cartilaginous fishes. IgNAR is a heavy chain homodimer that does not associate with light chains; instead it is capable of binding antigen with high affinity via a single variable domain (VNAR). Due to their small size, high stability and ability to target novel epitopes, such as active sites or deep clefts on the surface of proteins, there is much interest in developing VNARs as new diagnostic reagents and therapeutics. We have previously developed VNARs that could be used to detect anthrax bacteria and Ebola virus, and have ongoing projects looking at the utility of VNARs as diagnostics, imaging agents and/or therapeutics for cancer and other human diseases such as HIV.