Sarin, the nerve gas developed by the German military during World War II but never deployed, is among the most toxic chemicals known to man. Inhaled, death comes on in two to 10 minutes. Sprayed on skin, it penetrates without felt damage or sensation; it kills on entering the blood stream and paralyzes the muscles of breathing. The fatal dose of sarin is 0.01 mg per kg. That is, it takes only 70 or so mg to finish off a 170-pound man. These lethal agents work by blowing the fuses on cholinesterase, a crucial enzyme that largely controls the nervous system.

Since World War II, many countries, including the U.S., have stockpiled sarin as a hedge against possible chemical warfare. But the nerve gas came on stage only in March 1995, when Japanese cultists released it in the Tokyo subway system. It killed several people and incapacitated many more. Now it's back in the headlines because of suspicion that destruction of Iraqi sarin nerve-gas weaponry during the Gulf War sickened U.S. troops.

Gulf War syndrome is among the shiftiest maladies in the medical armamentarium. A constellation of self-reported complaints, it defies description and diagnosis. Symptoms are mainly neurologic, marked by impaired cognition, problems of attention, memory, reasoning, insomnia, depression, fatigue and headaches, experienced by 5,000 to 80,000 U.S. veterans after returning from Operations Desert Shield and Desert Storm in 1991.

The proximal cause of Gulf War syndrome is usually assigned to organophosphorus, the prime ingredient of nerve gas. But similar cholinesterase blockers incapacitate three million people a year worldwide, killing 220,000 of them. They die not from anti-personnel weapons but self-inflicted agricultural insecticides; a major concern to the Environmental Protection Agency.

Research at the Salk Institute in La Jolla, Calif., has identified a gene that apparently links certain pesticides and chemical weaponry to a number of neurological disorders, including the elusive Gulf War syndrome and ADHD - attention deficit hyperactivity disorder. The finding, published in the March 17, 2003, online version of Nature Genetics, is the first to demonstrate a clear genetic nexus between neurological disorders and exposure to organophosphate chemicals. The article is titled: "Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity."

Knockout Mice Weave Genetic Connections

The paper's senior author, Carrolee Barlow, found in mice that that organophosphate exposure inhibited the activity of a gene called Nte, which encoded the enzyme NTE. The inhibition either killed the mice before birth, or over time led to a range of behaviors very similar to ADHD. Some of the rodents' neurological problems also echoed many of the symptoms seen in Gulf War syndrome.

"There have been anecdotal links made between rises in ADHD, Parkinson's disease and other disorders and exposure to insecticides," Barlow told BioWorld Today. "But scientists have been focusing on enzymes that act on acetylcholine neurotransmitters," she continued. "Our study shows that there may indeed be a genetic connection that explains how organophosphates can cause these reactions. It's just not what we assumed it might be."

Barlow's team had originally been looking at how environmental factors, such as crop-spraying, immediately affect the nervous system. They found that mice bred without the Nte gene died during embryogenesis. The mice with only one Nte gene copy had a 40 percent decrease in the NTE enzyme produced by its gene. Control animals, harboring normal genes, also showed ADHD behavior, though to a lesser degree, when exposed to organophosphates. The gene is active in parts of the brain controlling movement, notably the hippocampus, cerebellum and spinal cord.

"Nte is a large gene, " Barlow observed. "It's possible that we all have slightly different forms of the NTE enzyme. This may explain why some may get ADHD when they're exposed at young ages, and why others may get Gulf War syndrome at a later age - or why some of us have no symptoms at all. It appears to be a case of delayed toxicity," she suggested, "inhibiting the function of NTE."

Besides immediate toxicity and death, organophosphates can also cause delayed damage to the nervous system - reminiscent of the Gulf War syndrome. Until now it was not clear how this slower damage occurs. To address this question, the Salk team created mice lacking either one or both copies of the Nte gene, which expressed NTE. Thus, their study demonstrates that poisoning by these toxins is due to a loss of NTE enzyme function.

As discussed in an accompanying "News & Views" commentary by James O'Callaghan at the Centers for Disease Control and Prevention, "these results do not support current theories of how organophosphates cause nerve damage." His editorial is headed: "Neurotoxic esterase: not so toxic?"

A Whiff Of The Gas That Gassed You

There are drugs administered to human patients that are organophosphates. They adjust the levels of the neurotransmitter that gets elevated too high - that's what kills you - if you have low levels in an autoimmune disorder called myasthenia gravis. It features weak, droopy muscles, especially in eyelids. A little dose of therapeutic nerve gas to raise the transmitter restores normality. Measured doses of nerve gas treat that condition. And there's paralysis that we don't notice until we're very old.

When you inhibit the acetylcholinesterase system that paralyzes your muscles, including the intercostal muscles that let you breathe, that's how you die. But if you have myasthenia gravis, there are probably cases of people taking medication from patients treated for that disease, who could actually develop paralysis because they have normal enzyme levels, and they should not be elevated. But against low levels one way to raise them is treating them with nerve gas in pill form.

There's also a classic antidote against nerve gas, namely, atropine, which has rather acute effects. The trouble with atropine - which the troops will doubtless carry in their packs - is that it protects the targets of acetylcholine. Unfortunately, it has side effects such as inability to sweat, and it blocks what the cholinergic nervous system does. But it's also a way of saving a soldier's life, especially if that antidote is in his first aid kit on his way into Iraq.