Scientists used accelerated evolution to develop enzymes that provide protection against nerve gas

January 24, 2011

Protection against nerve gas attack is a significant component of the defense system of many countries around the world. Nerve gases are used by armies and terrorist organizations, and constitute a threat to both the military and civilian populations, but existing drug solutions against them have limited efficiency.

A multidisciplinary team of scientists at the Weizmann Institute of Science succeeded in developing an enzyme that breaks down such organophosphorus agents efficiently before damage to nerves and muscles is caused. Their results have recently been published in the journal . Recent experiments performed in a U.S. military laboratory (USAMRICD) 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.

Nerve agents disrupt the chemical messages sent between nerve and muscle cells, causing loss of muscle control, and ultimately leading to death by suffocation. Nerve agents interfere with the activity of acetylcholinesterase, the enzyme responsible for the breakdown of the – acetylcholine. As a result, acetylcholine continues to exert its effect, resulting in constant muscle contraction throughout the body.

Several drugs exist that are used to treat cases of nerve agent poisoning. Although these drugs are somewhat effective when exposed to small doses of the nerve agent, they do not provide protection against high-dose exposure; they are not effective against all types of nerve agents; or they cause serious side effects. Neither are they able to prevent nor repair cerebral and motor nerve damage caused by the nerve agent.

An ideal solution to the problem is to use enzymes – proteins that speed up chemical reactions – to capture and break down the nerve agent before it gets the chance to bind to the acetylcholinesterase, thereby preventing damage. The main obstacle facing the realization of this idea, however, is that nerve agents are man-made materials and therefore, evolution has not developed natural enzymes that are able to carry out this task.

Scientists worldwide have previously succeeded in identifying enzymes that are able to break down similar materials, but these enzymes were characterized by low efficiency. Large amounts of the enzyme were therefore required in order to break down the nerve agent, rendering their use impractical.

This is where Prof. Dan Tawfik of the Weizmann Institute's Biological Chemistry Department enters the picture. Tawfik's group developed a special method to artificially induce "natural selection" of enzymes in a test tube, enabling them to engineer "tailor-made" enzymes.

The method is based on introducing many mutations to an enzyme, and scanning the variety of mutated versions that were created in order to identify those that exhibit improved efficiency. These improved enzymes then repeatedly undergo further rounds of mutations and selection for higher efficiency. In previous studies, Tawfik showed that this method can improve the efficiency of enzymes by factors of hundreds and even thousands.

For the current task, Tawfik selected an enzyme that has been extensively studied in his laboratory, known as PON1. The main role of this enzyme, found naturally in the human body, is to break down the products of oxidized fats that accumulate on blood vessel walls, thus preventing atherosclerosis. But PON1 seems to be a bit of a "moonlighter" as it has also been found to degrade compounds belonging to the family of nerve agents.

However, because this activity has not fully evolved and developed through natural selection, its efficiency in carrying out the task remains very low. But by using the directed evolution method, scientists hope that 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.

In the first phase, Tawfik and his team, including research fellow Dr. Moshe Goldsmith and postdoctoral student Dr. Rinkoo Devi Gupta, induced a number of mutations in PON1 – some random and others directed at key sites on the enzyme. To identify the most effective PON1 mutants, the scientists joined forces with Yacov Ashani of the Structural Biology Department.

The method that the scientists developed closely mimics what happens in the body upon exposure to nerve agents: They put the acetylcholinesterase in a test tube together with a specific mutant PON1 enzyme that they wanted to test, and added a small amount of nerve agent to it. In cases where the acetylcholinesterase continued to function properly, it could be concluded that PON1 rapidly degraded the nerve agent before it was able to cause damage to the acetylcholinesterase.

After several rounds of scanning, the scientists succeeded in indentifying active mutant enzymes, which are able to break down the nerve agents soman and cyclosarin effectively before any damage is caused to the acetylcholinesterase. These mutant enzymes have been structurally analyzed by a team of scientists from the Structural Biology Department, which included Profs. Joel Sussman and Israel Silman, and research student Moshe Ben-David. Further experiments have shown that when these enzymes were given as a preventative treatment before exposure, they afforded animals near-complete protection against these two types of nerve agents, even when exposed to relatively high levels.

The scientists plan to further expand the scope and develop preventive treatment that provides protection against all types of existing nerve agents. They are also trying to develop enzymes with high enough efficiency to be able to very rapidly break down the nerve agent so they could be used to prevent the lethal effects of by injection immediately after exposure.

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1 / 5 (5) Jan 24, 2011
evolution has not developed natural enzymes that are able to carry out this task

Time to play with words. So they decided to give evolution a hand since it's too slow and clumsy to come up with a solution to the problem all by itself. Now since man is supposedly a product of evolution one can go so far as to say that evolution has actually achieved it's purpose of creating an enzyme to disable another one of man's[and hence evolution's] more dangerous products. So evolution has successfully neutralised itself in this little game. I told you it's time to play with words.
One concern might well be that if one can develop such an effective neutraliser, one can also then develop an even more lethal nerve agent, using exactly the same method[s]. Further, the functions that PON1 performs might well have some unwanted side-effects if used in the fashion of the super-efficient new enzymes. This would only become apparent later. It usually happen that way.
5 / 5 (4) Jan 24, 2011
So they decided to give evolution a hand since it's too slow and clumsy to come up with a solution to the problem all by itself.
No, being dosed with nerve gas isn't really a gradual environment change, nor is it survivable when it is designed to destroy your biological chemistry in minutes.

Evolution isn't instantaneous, you should already know better than that. Just so you're completely aware, and because the statements of nerve gas provide a great bridge point for the topic...

Your denial of evolution is akin to Ahmedinjhad's denial of the holocaust.
5 / 5 (3) Jan 24, 2011
Clearly evolution is false since our bodies do not develop exoskeletons which prevent us from being killed by bullets as they're shot...

5 / 5 (2) Jan 24, 2011
This is great. I feel the evolutionary noose being tightened around the necks of the creationists.
5 / 5 (3) Jan 24, 2011
So they decided to give evolution a hand since it's too slow and clumsy to come up with a solution to the problem all by itself.
Wait, but I thought you completely rejected the idea of evolution. Are you starting to come around that evolution actually takes place, as is what happened in this article (whether "helped" or not)?
1 / 5 (2) Jan 31, 2011
hmm..."helped evolution"? Sounds nearly like an oxymoron;-)

So if someone says that they believe we are the product of evolution, perhaps one needs to start asking whether they mean "helped" or "unhelped".
not rated yet Feb 14, 2011
So if someone says that they believe we are the product of evolution, perhaps one needs to start asking whether they mean "helped" or "unhelped".

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