Friday, January 7, 2011

SYNTHETIC PLANT-DERIVED BIOSCAVENGERS ARE NOW A REALITY

Henricia spp.; marine scavenger
courtesty, commons.wikipedia.org

Imagine, our soldiers are at the battlefield and suddenly they realize a nerve agent is being used by the enemy, or a farmer goes to the hospital to complain of muscular pains and the doctor tells him he is suffering from organophosphate poisoning from the pesticides he is using. These two scenarios have become everyday that the effective protection and treatment for organophosphate poisoning is a vital concern for public health.

How do organophosphates poison the body? At the cholinergic receptors of the brain or the synaptic clefts of neuromuscular junctions, acetylcholine, a chemical released to transmit messages between neurons or cause the muscles to contract, binds to a receptor molecule and causes action potential to be transported that causes contraction. When the task of acetylcholine is complete, it has to be degraded quickly otherwise, after the first contraction, flooding of acetylcholine would lead to repeated contractions at the postsynaptic membranes, neuromuscular paralysis and death might eventually be the result due to respiratory and cardiac paralysis.

The body responds to these need to degrade acetylcholine using bioscavengers. These scavengers seek out unwanted molecules in the body and either neutralize them or destroy them. Two bioscavengers that are of interest in organophosphate poisoning are acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE).
Acetylcholinesterase is produced at the nervous system. It degrades acetylcholine to acetic acid and choline, therefore preventing an acetylcholine flood at choline receptors at the brain or synaptic clefts at neuromuscular junctions, while Butyrylcholinesterase (BChE) is produced at the liver and circulates in the blood of mammals and birds; its job is to search for molecules that desire to hinder or block the function of acetylcholinesterase (AChE). Butyrylcholinesterase (BChE) destroys agents that act as an anti-cholinesterase or blocks the activity of cholinesterase by scavenging the agent. BChE is more of medical importance than AChE because it can easily be extracted from the blood supply and stockpiled.

Organophosphate poisoning has become a threat of visible importance in today’s world. Pesticides are used regularly in farming in Africa and they cannot do without them. The allure of using a nerve agent is very high, especially for rogue or terrorist organizations, as these lethal nerve toxins are relatively easy and inexpensive to manufacture and store.

That is why a research led by Tsafrir Mor, a biochemist in the Center for Infectious Diseases and Vaccinology at the Biodesign Institute at Arizona State University, is very important. He and his team have shown that BChE can be synthesized from plants and is effective against both pesticide and nerve agent organophosphate poisoning.
Currently, treatment for organophosphate poisoning is atropine. It is a chemical that saves lives and can alleviate acute symptoms of the poison but it cannot meet to the challenge of curtailing the long-term neurological effect of such poisoning which may include muscle weakness, seizures and convulsions, permanent brain defects and social or behavioral symptoms.

On the other hand, although BChE if sufficiently high in the blood can work better than atropine, this is not always the case. The need to extract BChE and stockpile it in preparation for a warfare involving toxic nerve agents is therefore important but deficient. If BChE can be synthesized at the lab, then doctors can administer them to patients when needed and then save lives. Tsafrir Mor has successfully synthesized BChE using transgenic tobacco leaves. This means that he incorporated the genetic code for BChE from mammals into tobacco leaves which successfully produced the enzyme and then extracted the enzyme from the leaves.

According to Mor, BChE synthesis is a breakthrough research because to extract these enzyme naturally, a few thousand troops would involve the entire blood supply of a country like the United States of America. Furthermore, in addition to its possible treatment for cholinergic ailments resulting from organophosphate poisoning, BChE could be used post-surgery for patients who naturally lack the enzyme and have difficulty recovering from the effects of anesthesia. Also, there is high evidence which suggests that BChE could be useful for treatment of patients suffering from drug overuse and addiction, especially cocaine and most possibly, as a prophylactic or preventive measure, which would save so many lives lost to that habit, drug addiction.

The research was successful. Mor’s group could demonstrate successful protection from pesticide and organophosphate poisoning in two animal models. In addition, the synthesized enzyme, when coated with Polyethylene glycol (PEG) had an extended half-life which more closely replicated the persistence of naturally-derived BChE in the bloodstream, as a proof of the effectiveness of the synthesized BChE.

On the other hand, more work still have to be done. According to Mor, the synthesized BChE acts stoichiometrically, that is, every molecule of an anti-cholinesterase needs a molecule of the synthetic BChE. He aims to make the molecule work catalytically such that a little quantity of BChE is enough to destroy or scavenge enormous quantities of an anti-cholinesterase at and as needed, permitting for a low effective dose of the enzyme.
The scare of an attack the like of the sarin attack in the Tokyo subway system in 1995, perpetrated by the religiously-motivated group, Aum Shinrikyo, is a possibility that can not be ignored. If the world can gain more insight into understanding acetylcholine-linked diseases like Alzheimer’s Dementia, as well as be able to solve the drug problem that has become global, in addition to making biological warfare less threatening, then it would become a safer world, where science and technology should not be seen as a threat but as allies to human efforts to solve his medical and social problems.
Inspiration for this article: Plant-derived scavengers prowl the body for nerve toxins
Also: http://www.pnas.org/content/early/2010/11/05/1009021107

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