What began as a farfetched idea about chemicals jotted on a napkin has materialized into an antidote research project at Mississippi State University that’s on course to save thousands of lives.
MSU holds the patent for a set of compounds designed not only to counteract deadly nerve agents but also to prevent brain damage and other serious side effects of chemical exposure. One day in the future, antidotes developed from university research could be a revolutionizing leap ahead in the global research community’s race to render chemical weapons obsolete.
Jan Chambers, director of the MSU College of Veterinary Medicine’s Center for Environmental Health Sciences, remembers the moment well when she and her husband, the late Howard Chambers, were talking shop with a research colleague over lunch at a local restaurant. Their conversation turned to nerve agents, and a question was posed: What if we could develop a brain-penetrating oxime for the military?
“Howard said, ‘I’ve been thinking for years about this kind of chemistry,’ and he began taking notes on a napkin,” she recalls.
The Chambers were able to use phrases like “brain-penetrating oxime” in casual conversation because they were more than a devoted couple for nearly 50 years — they also were long-time research partners whose shared love of science reinforced their bond and eventually led to MSU’s pioneering research into nerve agent antidotes.
Howard Chambers spent his entire 48-year academic career at MSU, where he was a professor in the department of biochemistry, molecular biology, entomology, and plant pathology and established a research program in insecticide toxicology. He died unexpectedly after a brief illness on Dec. 3, 2016.
The Chambers’ knowledge of insecticide toxicology has been key in MSU’s antidote research. Some insecticides and nerve agents are chemical cousins that act by shutting down the central nervous system, which means MSU’s antidote compounds also can be used to treat victims of poisoning by some of these insecticides.
The proliferation of chemical weapons and their use on non-military targets have intensified the sense of urgency surrounding antidote research. In recent history, attacks involving the nerve agent sarin killed and injured scores of civilians in Syria and on the Toyko subway, and the nerve agent VX was the culprit in a high-profile assassination in Malaysia in 2017. In March 2018, a former British intelligence agent and his daughter were nearly fatally poisoned by the suspected Russian nerve agent Novichok.
Nerve agents are designed to kill quickly by inducing respiratory failure and they also cause seizures. Current antidotes act by restoring function to the respiratory system but cannot enter the brain to prevent or lessen seizures, meaning that even if antidotes are administered in time to save lives, survivors may suffer permanent brain damage — one of the most serious and irreversible side effects of chemical exposure.
“The seizures can kill brain cells” says Chambers. “That’s why we’re focusing on getting compounds into the brain to prevent seizures induced by nerve agents. If seizures are prolonged, we start getting permanent brain damage, and the brain doesn’t recover as easily as other tissues do.”
Evidence from a variety of experimental paradigms has shown that MSU’s compounds can reverse the negative effects of nerve agents, says Chambers. In a 2018 article in Science Magazine, MSU was one of only three research entities in the U.S. recognized for innovative work in the field of brain-penetrating oximes.
Initially, MSU conducted research via a grant from the Department of Defense’s Defense Threat Reduction Agency that led to a successful patent application. Since then, the team has operated on funding from the National Institutes of Health to protect civilians. Chambers hopes to eventually gain FDA approval for the antidote compounds, a lengthy process that relies on sustained funding sources to keep research moving forward. (MSU does not stock nerve agents on campus; surrogate compounds are used for all research activities.)
Even though they face a long road ahead, Chambers and her fellow researchers know the journey will be worth it. They envision a number of proactive applications for MSU’s compounds, from protecting soldiers on the battlefield to helping first responders in harm’s way to strengthening the CDC’s Strategic National Stockpile of pharmaceuticals to protect against chemical weapons.
Understandably, Chambers’ commitment to the project is also personal.
“I promised Howard that we would continue working on his antidotes as long as they continue to show promise,” she says. “He loved being in the lab and synthesizing new compounds, and he was thrilled that some of his ideas for antidotes were actually working.