More about the science
Accidental exposure to organophosphate (OP) pesticides is frequently encountered in hospital emergency rooms, particularly in the developing world. These deadly chemicals are also a favored means of suicide in poor, agricultural regions. Pubic health concerns are compounded by the potential use of highly lethal organophosphate concoctions as instruments of terror or biowarfare agents. Organophosphate acts to disrupt neurotransmission, inhibiting synaptic acetylcholinesterase (AChE-S), leading to the accumulation of acetylcholine in the synapse and neural over-stimulation.
First employed as potent insecticides, OPs were subsequently adapted as chemical warfare (CW) agents. The first military grade OP “nerve gases”, tabun, sarin and soman, were produced in Nazi Germany. More toxic variants were to follow during the cold war, including VX, Russian-VX and cyclosarin. Such agents are generally easy to produce, given facilities and know-how, and can be stored and weaponized without great difficulty.
Depending on the dosage received, the victim of organophosphate exposure may quickly succumb to cardiovascular and respiratory collapse. Those surviving OP poisoning are frequently subject to long term sequelae, including delayed neuropathy, muscle weakness, permanent brain injury and sometimes behavioral deficits.
Such delayed consequences of OP poisoning are not addressed by existing medical treatments. The use of human proteins as bioscavengers of organophosphate (OP) has emerged as an attractive alternative to existing toxin antidotes, both as preventative intervention and for post-exposure treatment for chemical warfare nerve agents.
A class of bioscavengers (BSCs) known as human cholinesterases (ChEs) have met with considerable clinical success in binding to and sequestering organophosphates. Unfortunately, nerve toxins are able to inactivate these ChEs unless they are additionally supplied with enzymes required to catalyze the degradation of OPs. One such important enzyme, butyrylcholinesterase (BChE)—can be isolated in limited quantity, from human plasma. The enzyme may be used in clinical trials to test its safety and efficacy for biodefense. But broad-based defense from OPs will ultimately require the cost-effective development of a new generation of BSCs that can catalytically degrade organophosphate.
This project team is developing a novel means to biomanufacture recombinant BSCs based on the human proteins AChE, BChE and PON1 using plant-based systems. This approach has several advantages:
- Scope: transgenic plants can provide an unparalleled variety of recombinant products
- Cost: plant-produced cholinesterases are inexpensive to produce and store
- Scale: Agriculture provides an efficient means of mass production
- Safety: No contaminating human pathogens or prions are present
Transgenic plants are being evaluated in Mor’s laboratory as a source for recombinant human acetylcholinesterase to provide protection from pesticide poisoning and biowarfare agents. Among the challenges facing the Mor group are (a) identification of appropriate protein targets for which other production systems do not exist or have significant limitations (b) continuous development of robust, fast, and agronomically and environmentally sound plant-expression systems (c) study of plant molecular processes, especially post-translational modifications, to enable their manipulation (d) pre-clinical and clinical testing of the plant-produced protein pharmaceuticals for their safety and efficacy and finally (e) use of these new insights for the development of the next generation of protein pharmaceuticals.