Biodesign Institute takes part in $14.4 million NIH Chemical Defense Grant

Biodesign Institute takes part in $14.4 million NIH Chemical Defense Grant

February 9, 2007

February 8, 2007

Joe Caspermeyer, Media Relations Manager & Science Editor
(480) 727-0369 | joseph.caspermeyer@asu.edu
February 9, 2007


Researcher Tsafrir Mor advancing plant-based production of new antidotes against nerve agents

The Biodesign Institute at Arizona State University has been awarded one of six research projects as part of a $14.4 million National Institutes of Health (NIH) effort to develop improved antidotes for civilian populations vulnerable to chemical agent poisoning by a terrorist attack.

The overall effort is dubbed the CounterACT (Countermeasures Against Chemical Threats) Center of Excellence. The program is led by David Lenz, PhD, of the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD).

Tsafrir Mor, a researcher at ASU’s Biodesign Institute and assistant professor in the School of Life Sciences, will be the lead investigator of the five-year, $2.67 million ASU portion of the award.

“Nerve agents, such as sarin, are among the most lethal chemical weapons ever developed. They have been used in wars as recently as the 1980s and by terrorist organizations such as the subway attacks in Japan in the mid 1990s” said David Moore, DVM, PhD, Director, Strategic Research Program Development, USAMRICD, at Aberdeen Proving Ground, Maryland. “The work of this new center will lead to a paradigm shift in how to treat nerve agent exposure.”

Besides the terrorist threat, Biodesign’s Mor points out that the active chemical ingredient contained in nerve agents, organophosphates, can be found in many pesticides, leading to the accidental death of an estimated one to two million individuals worldwide who don’t properly handle pesticides.

Mor’s project is based on two interlocking themes, one focused on the design of human enzymes with new activities to neutralize nerve agents and a second utilizing plants to express proteins of human origin in high quantities.

The project, “Rapid and Large Scale Plant-Derived Production of Catalytic Nerve-Agent Bioscavengers” is a natural progression of Mor’s previous work that was supported by the Defense Advance Research Project Agency (DARPA)

“In our DARPA project,” said Mor, “we engineered plants to express the natural target of these toxins, the enzyme acetylcholinesterase, and proved that the plant-derived protein is effective in protecting against pesticide poisoning.”

Preclinical studies have shown that a family of human proteins, called cholinesterases (ChEs), is an effective antidote against nerve agents. The enzymes act like “molecular sponges,” soaking up and neutralizing the harmful organophosphates before they do damage.

The new project focuses on developing “next-generation” antidotes, called bioscavengers.

“The new candidate bioscavengers we hope to develop are human enzymes that not only bind to nerve agents to neutralize them, but also destroy them,” said Mor. ,“We can use plants and new technologies developed at ASU to scale-up production to make large amounts of antidote material in a cost-effective manner.”

Nerve agents achieve their lethal effects by shutting down the control of the body’s peripheral nervous system, including control of glands, internal organs and skeletal muscles. This nervous system has a vital, sweeping scope, from the dilation of the pupil in the eye, through excretion of tears and saliva to powerful muscle contractions in the gut, heart and lungs. Consequently, nerve agent poisoning can lead to more severe symptoms like involuntary excretion, tremor, paralysis and death.

The trigger behind the muscle contractions is a chemical messenger, acetylcholine, which communicates and transmits signals between nerves, and between nerves and target cells like muscles. Many steps are necessary for proper nerve signaling, but a key step is to whisk acetylcholine away from the nerve by an enzyme called acetylcholinesterase (AChE). Otherwise, the body’s cholinergic system can quickly spiral out of control.

Mor is most interested in a chemical cousin of AChE, called butyrylcholinesterase (BChE), which is found in serum plasma and the liver. BChE can also degrade acetylcholine, but it also seems to play a role as the body’s vacuum cleaner, degrading drugs and natural products and eliminating them from the body. Another enzyme, paraoxonase (PON1) is a constituent of HDL, the body’s “good cholesterol” and has a role in prevention of atherosclerosis.

“If we can catalytically neutralize these poisons using BChE or PON1, the real advantage will be that we won’t need as much of the enzymes,” said Mor. “Plus, there may be benefits to conditions such as heart disease through gaining an increased knowledge of how BChE works to clear potentially harmful items from the body.”

ChEs can be purified from the blood to use as a nerve agent antidote. However, large amounts are needed for full protection, and the only source is outdated blood-banked plasma.

But using blood banks as the main source of ChEs is out of the question.

According to Mor, ChEs are present in such tiny quantities that he estimates it would take the entire blood supply of the U.S. just to produce one kilogram of material.

Therefore, Mor, a protein engineering and plant-based therapeutics expert, will initially adapt plants as protein production factories to develop a novel means to biomanufacture catalytic bioscavengers based on the human proteins BChE and PON1.

Mor recently completed his four-year award from the Defense Applied Research Projects Administration (DARPA) to develop ideas of using plants as a bioproduction system for countermeasures against chemical warfare agents. His plant of choice is tobacco, because it is a non-food crop. According to his calculations, he can create enough ChEs with the system and scale it up accordingly to supply the entire U.S. in about 100-1000 acres, depending on the protein yield per plant.

At the end of the new grant period, Mor is hopeful that his approach will lead to new effective and safe countermeasures to protect humans from the toxic effects of pesticides and nerve agent exposure at a fraction of the current dose of human BChE and at a fraction of the costs.

 

Written by: Joe Caspermeyer