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Summary

Work in my laboratory is primarily concerned with developing disruptive technologies for the detection and inhibition of high consequence pathogens and toxins.  One aspect of this is the pursuit of antibodies capable of threat recognition in a highly specific and sensitive manner suitable for transition to biosensors and field portable diagnostics.  When we talk of field portable diagnostics and detection systems, the spectrum of operating conditions they face is enormous.  The harshest conditions are usually found in resource poor areas of the world were electricity and refrigeration are rare, and re-supply is difficult.  Such areas require extremely rugged yet simple to operate single-use (dipstick) systems with long shelf-lives.  Harsh conditions still exist on the homeland front in a different way, due to the need for constant real-time environmental monitoring of biothreats in multiplex.  A highly promising antibody format with the potential to offer a solution to these problems is the single domain antibody (sdAb or nanobody).

We have generated sdAb specific for Marburgvirus which is a highly lethal hemorrhagic fever virus sporadically yet explosively emerging in Africa, which has been imported to the US recently and is also a CDC “bioterror” threat.  Our sdAb appear to match the sensitivity of current detection systems yet are refoldable and therefore more stable and we are currently adapting these to field portable systems.  More recently, we have also applied the methodology to the Ebolavirus group, close relatives of Marburgvirus posing similar risks.  Again, we have isolated very sensitive yet rugged sdAb capable of recognizing all species currently known (manuscript in preparation) which should enable the assembly of comprehensive Filoviral tests.

Another group of biothreats we have been targeting are the botulinum neurotoxins which are the most poisonous substance currently known, estimated to be 100 billion times more toxic than cyanide.  The toxins are synthesised by certain species of spore forming anaerobic Clostridia bacteria as a variety of immunologically distinct “serotypes” with some of these having several distinguishable “subtypes”.  We have recently succeeded in engineering a heptaplex assay for the 7 known serotypes based upon sdAb, all of which we show to be refoldable and suitable for ruggedising multiplex biosensor platforms.

Our research is also leading us from applied to basic science as we ask, “how do our sdAb target biothreat antigens so effectively”.  And, in order to understand antibody-antigen recognition at the molecular level we are using site directed mutagenesis, in vitro evolution, molecular modeling and X-ray crystallography (the latter with kindly collaborators at UTHSCSA).  As part of this effort we are studying a highly unusual sdAb that appears to autocrystallise within hours and as yielded a 1.8 A resolution structure.

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