Joshua Weinstein

Systems and Approaches
Single cell gene expression, control of partially observable systems, large scale integration, irreverence

Interests
Adaptive immunity, stochastic modeling, repertoire kinetics, data mining

Summary
I'm interested in the application of physical models to real world phenomena, in particular those that are dominated by stochastic behavior on short timescales while behaving deterministically on long timescales. The adaptive immune system is a fascinating manifestation of this in biology. It serves to enable a single individual to defend against previously unencountered pathogens. According to the reigning paradigm in immunology, an individual will find a defensive solution by trial and error: randomly recombining and mutating sequences coding for pathogen-binding proteins, known as antibodies and T-cell receptors. Obtaining a deep understanding of how this happens so reproducibly remains one of biology's major open problems. My approach to this problem uses high-throughput sequencing to determine the collective "repertoire" of immune receptors. Sequencing costs have experienced exponential decay over the past several years, and the quality of sequence output has itself experienced a rapid increase. This means that subtle variation within populations of sequences is only now becoming observable to researchers. My work can be classified under two headers. On the one hand, I am interested in the basic governing dynamics of the immune system, ie how do immune cell lineages explore the space of possible receptor sequences, and what are the physical limitations they encounter in finding the solution in such a short time? This has led me to make heavy use of a simple model organism, the zebrafish. On the other hand, I am interested in exploiting this reductionism to facilitate our understanding of diseases in humans. I hope to apply this understanding to the development of powerful diagnostic and prognostic tools by making an individual's immune "memory" an open book for both clinicians and laboratory scientists.