OSU researching enzyme for use in biological attack

The National Institutes of Health is banking on groundbreaking research looking into a natural defense to neurotoxins being done at Ohio State University.
 
In December, the NIH announced a $7.5 million grant to fund a collaboration between the university, the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) and Israel's Wiezmann Institute of Science to genetically engineer that defense from an enzyme already present in the human body.
 
The goal: To genetically enhance the enzyme, boosting the ability of paraoxonase to break down toxins before they attack the nervous system and, ultimately, offer a defense against nerve agents that might be used on the battlefield, the weapon in a terror attack or the result of an industrial accident.
 
"It's a very exciting project--really great fundamental science with very important applications," says OSU's Tom Magliery, co-principle investigator for the study.
 
Nerve agents, such as sarin or chlorine, are phosphorus-containing organic chemicals. When they come in contact with the human body, they bond with the enzyme acetylcholineterase, which transmits chemical messages from the brain to the rest of the body. They disrupt that ability, leading to paralysis, asphyxiation and, unchecked, death.
 
Paraoxonase, however, has shown limited ability to intercede, scavenging the toxins from the blood stream and breaking them down into harmless chemicals before they can do damage, says Magliery.
 
"It's not nearly efficient enough to do it in its natural state, or we'd be immune to nerve agents already. What we have to do is engineer a more efficient form of the enzyme," he adds.
 
As with most science, that's more easily said than done. In this case, that's because so little is known about the enzyme.
 
"We really don't know what it does, why it's in our blood. Its purpose is to  degrade some molecule that is important to our physiology, but science hasn't discovered what that target is yet. It's an unknown," Magliery says.
 
What is know is that paraoxonase was shown in an earlier NIH study to be the best hope to achieve the goal of finding a treatment for nerve agent victims.  OSU participated in that study with experts from around the country. That five-year project examined several enzymes' abilities to break down specific nerve agents, like sarin, called "G-agents."
 
The latest NIH grant is funding an extension of that earlier work, bringing together OSU and its partners into a Center for Excellence, dubbed the Center for Catalytic Bioscavenger Medical Defense Research II.
 
The meta-center's work at OSU taps into several scientific disciplines, a complex combination of mathematics, computer modeling, biochemistry and genetic engineering.
 
Part of the research team, led by OSU Division of Natural and Mathematical Sciences associate dean Christopher Hadad, is mapping the enzyme, looking at how and where to add molecules to boost its nerve agent-fighting capability. That, in itself, is an impressive task.
 
Their work, involving millions of computations and variables, is being done at the Ohio Supercomputer Center in Columbus. With the center's new, $4.1 million supercomputer called the Oakley Cluster, the system has the ability to perform 88 trillion calculations per second — far beyond the abilities of even the highest-end commercially available mainframes.
 
The complexity of their work demands such computing power.
 
"People who do biological simulations often are starting with a (known) structure of the existing enzyme. What's hard about our project is that there is no (known) structure. The only structure we have is not the human form, but what's called a chimera—its genes are 60 percent rabbit, 30 percent rat and 10 percent human," Hadad explains. "We're taking this non-human form and doing reverse mutagenesis, working backwards to figure out how the enzyme reacts to different molecules."
 
The simulations, "docking" different molecules into 20-50 structures at a time within the enzyme, not only predict the reactions but also help map out what changes can be made to the enzyme to make it more efficient, says Hadad.
 
Armed with that information, Magliery's team then works to duplicate the projections in the lab and test them against simulated nerve agents, with Hadad's team back-checking the results.
 
When the research group finds a promising result, its work is sent to USAMRICD for clinical evaluation with live nerve agents at its Aberdeen Proving Ground in Maryland.
 
The project's ambitious, not only for its goal — few enzymes have been converted into usable drugs to date — but also the obstacles that lie ahead.
 
"Enzymes naturally have only one function, one thing that it does very well, but we're trying to come up with something that will break down all types of nerve agents — one enzyme that does many things well," says Hadad.
 
Success could mean a medical miracle for thousands of patients accidentally poisoned with toxins every year, and the difference between a tragedy or a catastrophe if terrorists use nerve agents in an attack. It could also mean life or death to troops in the battlefield.
 
"If we're able to create a protein drug from this project, it could be used in two ways: it could be used to treat people after they've been exposed, whether by accident or the result of an attack," says Magliery, "or it could be used prophylactically, given to people going into an area where they risk exposure. People like soldiers or first-responders."