By Chris Healey
Bioscavengers are naturally-occurring proteins capable of effective nerve agent elimination. They are currently theoretical or in the early stages of clinical trials. However, they have the potential to revolutionize the prevention of nerve agent poisoning.
Discovered by German chemists researching insecticides in the 1930s, nerve agents were quickly recognized as a potential weapon. Nerve agents were produced and stockpiled by the Germans during World War II but were never used. Their first use during wartime occurred during the Iraq-Iran conflict in the 1980s. Iraq reportedly released nerve agents against Iranian troops and later against members of its Kurdish population.Nerve agents were recently used during Aum Shinrikyo’s Tokyo subway attack in 1995, and again in 2013 by the Assad regime during the Syrian Civil War.
The nervous system controls muscle contraction through release of neurotransmitters into neuromuscular junctions, which are media between neurons and muscle fibers. Acetylcholine is the primary neurotransmitter involved in muscle contraction.
Nerve agents bind and inactivate acetylcholinesterase, a regulatory protein of acetylcholine within neuromuscular junctions, thus preventing acetylcholine dismissal. Acetylcholine accumulation leads to salivation, sweating, abdominal cramps, muscle twitching, and flaccid paralysis. Death occurs from inadequate respiratory function as a result of neuromuscular junction disruption in the diaphragm.
Distinguishing prophylaxis from pretreatment is important in nerve agent countermeasure discussion. Pretreatment is any therapy administered before poisoning so that treatment after poisoning can be more effective. Prophylaxis is pretreatment that does not require additional intervention. In other words, prophylaxis eliminates the need for treatment after poison exposure.
The necessity of pretreatment limits the efficacy of conventional nerve agent treatments. Nerve agents rapidly cause irreversible damage within neuromuscular junctions. The presence of a pretreatment such as pyridostigmine, an acetylcholinesterase inhibitor, helps minimize damage before post-exposure treatment can be administered.
Atropine and oximes—post-exposure treatments for nerve agents—have limited efficacy. They are toxic if administered in the absence of nerve agents. Furthermore, they must be administered very shortly after nerve agent exposure to have any therapeutic effect. If administered following a pretreatment, and in a timely manner after nerve agent exposure, atropine and oximes can prevent death. Incapacitation, convulsions, and long-term neurologic damage, however, are unavoidable despite treatment.
Bioscavengers function as a prophylaxis. Damage to neuromuscular junctions only occur in the presence of nerve agents. In other words, bioscavengers eliminate the need for atropine and oximes, while nullifying any chance of long-term neurologic damage.
Although everyone possesses trace amounts of bioscavengers in their bloodstream, innate levels are too minute to ward off physiologically-significant nerve agent quantities. Bioscavengers must be extracted from enormous amounts of human plasma and administered in a concentrated regimen to counter nerve agent exposure. Harvesting bioscavengers from plasma is costly, inefficient, and impractical as a means of production. More efficient production methods, such as harvesting molecules from the milk of transgenic goats, are currently under investigation.
Current bioscavengers are considered stoichiometric, meaning each bioscavenger molecule can only eliminate one nerve agent molecule. To be effective, there must be enough stoichiometric bioscavengers in the bloodstream to eliminate the amount of nerve agent concurrently present.
The prophylactic nature of bioscavengers, compounded with the rapid effect of nerve agents, render them useless if administered after nerve agent exposure. Strict use as a prophylaxis limits therapeutic utility. For example, it would be impossible to administer bioscavengers to victims of a terrorist attack involving nerve agents prior to the event. However, bioscavengers would be extremely valuable to first responders as they potentially expose themselves to nerve agents in that situation. Furthermore, soldiers and others in war zones anticipating a nerve agent attack could administer bioscavengers to proactively neutralize that threat.
A catalytic bioscavenger is a theoretical concept that improves upon stoichiometric limitations by exploiting enzymatic behavior. Instead of a one-to-one ratio, whereby a bioscavenger eliminates itself by binding to a nerve agent, catalytic bioscavengers would be capable of eliminating many nerve agents over time. In other words, catalytic bioscavengers would not only be able to eliminate large amounts of nerve agent during a single exposure, but would also maintain functionality through multiple exposures. Catalytic bioscavengers would eliminate therapeutic re-administration for continued nerve agent protection following initial exposure. While enzymatic utility may be frivolous for use in first responders, that function would be advantageous to those in situations involving multiple nerve agent attacks.
Methods to create catalytic bioscavengers are under investigation. Researchers are studying the protein structure of stoichiometric bioscavengers to see how it can be altered to form an enzyme. Once appropriate alterations to its chemical composition have been identified, genetic instructions can be created to produce desired results in a transgenic organism.