Safeguarding public health from nerve toxins

A class of compounds known as organophosphates (OPs) are among the deadliest nerve agents in existence. They take effect by disabling the nervous system’s ability to clear away neurotransmitters, causing continuous nerve activation, prolonged muscle contractions, cardiovascular and respiratory collapse. Organophosphates are prevalent in many pesticides and are a leading cause of accidental poisoning worldwide. More frighteningly, organophosphate toxins have been developed into weaponized nerve agents that can be used against human populations, with catastrophic consequences.

At the Biodesign Institute, researchers are taking bold steps to combat the growing threat of accidental or deliberate organophosphate poisoning from pesticides or lethal nerve agents like sarin and VX. In the laboratory of Dr. Tsafrir Mor, this work involves the innovative use of plants as living factories to produce potent nerve agent antidotes.

Normally, human proteins like acetylcholinesterase (AChE) act as bioscavengers, patrolling the body and cleaning up toxic organophosphates before they can cause harm. OP nerve agents however, can act to disarm these bioscavengers, leaving the victim without defense as unregulated neurotransmitter molecules accumulate in the victim’s synapses. The result, known as a “cholinergic crisis” leads to prolonged muscle contractions and fatal paralysis of respiratory organs.  Such deadly organophosphate weapons have been used during Iraq’s war with Iran and more recently, in terrorist attacks in the Tokyo subway in the mid-1990s.

The project team is attempting to use plants to synthesize bioscavenging proteins in sufficient quantity that they may be used to prevent or more effectively treat OP poisoning. To date, the most successful bioscavengers under study are human cholinesterases (ChEs), which mop up excess particles of the neurotransmitter acytylcholine, preventing it from building up in the synaptic spaces between nerves. Once synthesized in plants, these bioscavengers may be introduced into the human body where they not only bind with and neutralize nerve agents but actually break down and destroy the organophosphate poison.

Two critical bioscavengers under study in this project are butyrylcholinesterase (BChE), present in blood serum plasma and the liver and paraoxonase (PON1), found in high-density lipoprotein or HDL. By using plants as industrial protein production sites, Mor believes significant quantities of these bioscavengers can be efficiently manufactured. He estimates that 100-1000 acres of transgenic crop plants may be sufficient to supply the entire U.S. with an antidote stockpile against biowarfare agents.

Success in this endeavor would be a significant boon to society. Existing preventative measures, such as the use of the drugs pyridostigmine and atropine to reverse the effects organophosphate poisoning, carry serious risks to health. Research at Biodesign offers the prospect of a single protective drug candidate, free of harmful effects which can provide protection from nerve agents and prevent post-exposure incapacitation. 

Project funding:NIH, DARPA

Collaborators:

• US Army Medical Research Institute of Chemical Defense (USAMRICD, Aberdeen Proving Ground, MD)
  
• Ohio State University, (Columbus, OH)
  
• Human BioMolecular Research Institute, (HBRI, San Diego, CA)
  
• Hebrew University of Jerusalem, (Jerusalem, Israel),
  
• The Weizmann Institute, (Rehovot, Israel)