Development makes it more possible to survive nerve gas

New Worlds: Weizmann Institute team succeeds in developing enzyme that breaks down organophosphorus nerve agents before muscle damage.

By JUDY SIEGEL-ITZKOVICH
Lab 311 (photo credit: Bloomberg)
Lab 311
(photo credit: Bloomberg)
Protection against nerve gas is a main part of the defense system in many countries, as the toxic substances are a threat to both military and civilian populations. However, existing drug solutions have limited efficiency. Now a multidisciplinary team at the Weizmann Institute of Science in Rehovot has succeeded in developing an enzyme that breaks down such organophosphorus nerve agents before damage to nerves and muscles is caused.
Their results have been published in Nature Chemical Biology. Recent experiments performed in an American military lab have shown that injecting a relatively small amount of this enzyme into animals provides protection against certain types of nerve agents, for which current treatments show limited efficacy.
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Nerve agents disrupt the chemical messages sent between nerve and muscle cells, causing loss of muscle control and ultimately leading to death by suffocation, and interfere with the activity of acetylcholinesterase – the enzyme responsible for the breakdown of the chemical messenger called acetylcholine. Acetylcholine continues to exert its effect, causing constant contraction of the body’s muscles.
There are several drugs used to treat nerve agent poisoning; although they are somewhat effective when exposed to small doses of nerve agent, they don’t provide protection against high-dose exposure; they aren’t effective against all types of nerve agents, or they cause serious side effects. They also cannot prevent or repair cerebral and motor nerve damage.
An ideal solution to the problem is using enzymes – proteins that speed up chemical reactions – to capture and break down the nerve agent before it has the chance to bind to the acetylcholinesterase. The main obstacle is that nerve agents are manmade, and evolution has not developed natural enzymes able to do this. Scientists worldwide have succeeded in identifying enzymes able to break down similar materials, but these are not highly efficient.
Large amounts of the enzyme are therefore required in order to break down the nerve agent, rendering their use impractical.
Prof. Dan Tawfik of the institute’s biological chemistry department and colleagues developed a method to artificially induce “natural selection” of enzymes in a test tube, enabling them to engineer tailor-made enzymes. It’s based on introducing many mutations and scanning the variety of mutated versions created to identify the most efficient. These improved enzymes then undergo further rounds of mutations and selection for higher efficiency. Tawfik chose a natural body enzyme called PON1 that has been extensively studied in his lab and whose main role is to break down the products of oxidized fats that accumulate on blood vessel walls, thus preventing atherosclerosis. But PON1 has also been found to degrade compounds in the family of nerve agents.
By using “directed evolution,” scientists hope they will be able to evolve this random “moonlighting” activity into PON1’s main “day job,” which would be carried out more quickly and efficiently than before. After several rounds of scanning, the scientists succeeded in identifying active mutant enzymes able to quickly break down the nerve agents soman and cyclosarin. Tests have shown that when these enzymes were given before exposure, they gave animals almost complete protection against these two types of nerve agents.
Remembering Ilan Ramon
Every February, a US-Israel conference on space is held here in memory of Ilan Ramon, the first Israeli astronaut, who tragically died with his six colleagues in the 2003 failed US National Aeronautics and Space Admission flight Columbia.
At the latest meeting, a joint NASA-Israeli project to send a remote sensing mission to Venus was discussed. Dr. Jacob Cohen, the NASA AMES Research Center deputy chief of mission design, said during a visit to BGU that NASA was very interested in international collaborations. The late Israeli fighter pilot was a native of Beersheba.
Cohen and Prof. Dan Blumberg, head of BGU's Earth and Planetary Image Facility and a researcher with a long-time record of collaboration with NASA, are leading an Israeli-USA team that includes NASA, BGU, Houston’s Lunar and Planetary Science Institute, Israel Aerospace Industries and Northrop Grumman. A decision on whether to launch a radar mission to Venus is expected within a few months.
“The winning proposal will have three years and over $400 million to design and implement a science-led mission, with the goal of answering questions about the evolution of Venus,” said Blumberg. “We are using existing technologies... that include a very sophisticated radar system which is significantly lighter than any similar system in the world. The weight makes a huge difference when you’re trying to reach Venus,” he continued. Blumberg is sure that the fact that the Israeli-USA program is based on existing technologies currently in use in the Israeli satellite TecSAR gives this group a unique advantage.
Cohen said the team decided to use radar remote sensing to overcome the difficulties in sending a lander to Venus, where high temperatures and massive cloud cover have limited optical imaging of the surface, and the current proposal uses much higher resolution and better technology than all earlier missions.
“Venus has clouds, so you can't see what’s happening on the surface, and it is too hot, so long wavelengths are the solution,” he said.