Scientist studied agonizing death by nerve gas
By Tom Avril | The Philadelphia Inquirer | Published: September 5, 2013
PHILADELPHIA - Within seconds, your muscles become paralyzed, so you cannot breathe. Then come intense vomiting and likely seizures. The heart stops beating.
As the world debates its response to the alleged nerve gas attacks in Syria, one thing is clear:
It is an awful way to go.
One person who knows this better than most is Paul H. Axelsen, a professor at the University of Pennsylvania's Perelman School of Medicine.
In 1993, while on sabbatical at the Weizmann Institute of Science in Israel, Axelsen helped figure out how a key enzyme plays a role in communication between certain kinds of nerve cells - the very process that sarin gas interferes with so catastrophically.
Among the nerve cells affected by sarin are those that control our muscles. Inhaling the gas causes the nerve pathway to be switched on permanently, flooding the system with noise so that communication between nerve cells is impossible.
"It's almost a total-body malfunction," Axelsen said.
He studied how the enzyme works, in collaboration with Weizmann scholars who had previously determined the enzyme's structure. These researchers included Israel Silman and Joel L. Sussman.
The scholars did not specifically study sarin gas, developed by a German chemical company in the mid-1930s. Instead, theirs was a more fundamental study of how the enzyme, called acetylcholinesterase, worked in healthy people.
Still, the connection to nerve gas was on their minds, Sussman recalled in an interview Tuesday. His and Silman's original work on the enzyme's structure was published in 1991, soon after the end of the first Gulf War. Some of the research funding came from the U.S. Department of Defense, which sought information on how it could better protect soldiers in a gas attack, Sussman said.
The research also helped explain the potential for a class of drugs called cholinesterase inhibitors, which were then in development. These medicines, such as Aricept, can help ease the symptoms of Alzheimer's disease, though their impact is modest.
In a 1994 interview with The New York Times, Sussman recalled the moment that he and colleagues made their initial discovery, using a technique called protein crystallography. It was 3 a.m., and on a computer screen, they had successfully pieced together the 4,000 or so atoms that make up one molecule of the enzyme.
"I can only compare it to first seeing a new continent," Sussman said at the time.
Then Sussman, who had met Axelsen while visiting the Mayo Clinic, invited him to come to Israel to help determine how the enzyme did its job.
They knew the key to healthy communication between the nerve cells was a neurotransmitter called acetylcholine.
In order for a signal to be transmitted, acetylcholine is released by one nerve cell and is taken up by the next. The research team determined how the signaling chemical was broken down by the enzyme so that another signal could be sent.
"You need to stop the signal so that another signal can come," Axelsen said. "You do not under any circumstances want a signal to be permanent. These nerve gases permanently knock out the enzyme so that our nerve signals do not stop."
The Alzheimer's drugs work in a much more limited fashion. They also interfere with the enzyme's activity, but the effect is much weaker and also temporary - merely allowing a bit more time for a signal to be completed before the next one is sent.
Sarin, on the other hand, locks onto the enzyme and does not let go. It is in a class of compounds called organophosphates, which includes some pesticides.
For a person exposed to sarin, the situation is bleak. One antidote is a compound called atropine, which helps to dislodge acetylcholine from nerve cell receptors so they can once again receive a signal, Axelsen said.
Silman, of the Weizmann Institute, said Israeli citizens are given kits with autoinjectors that contain atropine and two other ingredients: anticonvulsant medicine and a reagent that can reactivate the key enzyme. These can be administered in advance, if there is warning of an attack.
Better antidotes and pretreatments are under development at the institute, Silman and Sussman said.
Atropine and the other current treatments are at best a partial solution, and only if administered immediately, Axelsen said.
"The reason it's used as a warfare agent is such small amounts go a long way," Axelsen said. "By the time you realize what's happening to you, you don't even have the presence of mind to get an antidote."