Troops who had genes that help metabolize sarin nerve gas were less likely to develop symptoms.
For three decades, scientists have debated the underlying cause of Gulf War illness (GWI), a collection of unexplained and chronic symptoms affecting veterans of the Persian Gulf War. Now researchers led by Robert Haley, M.D., Professor of Internal Medicine and Director of the Division of Epidemiology at The University of Texas Southwestern Medical Center (UT Southwestern), have solved the mystery, showing through a detailed genetic study that the nerve gas sarin was largely responsible for the syndrome.
The findings were published on May 11, 2022, in Environmental Health Perspectives, a peer-reviewed journal supported by the National Institute of Environmental Health Sciences, with an accompanying editorial on the paper by leading environmental epidemiologists.
Dr. Haley’s research group not only identified that veterans with exposure to sarin were more likely to develop GWI, but also found that the risk was modulated by a gene that normally allows some people’s bodies to better break down the nerve gas. Gulf War soldiers with a weak variant of the gene who were exposed to sarin were more likely to develop symptoms of GWI than other exposed veterans who had the strong form of the gene.
“Quite simply, our findings prove that Gulf War illness was caused by sarin, which was released when we bombed Iraqi chemical weapons storage and production facilities,” said Dr. Haley, a medical epidemiologist who has been investigating GWI for 28 years. “There are still more than 100,000 Gulf War veterans who are not getting help for this illness and our hope is that these findings will accelerate the search for better treatment.”
In the years immediately following the Gulf War, more than a quarter of the U.S. and coalition veterans who served in the war began reporting a range of chronic symptoms, including fatigue, fever, night sweats, memory and concentration problems, difficulty finding words, diarrhea, sexual dysfunction, and chronic body pain. Since then, both academic researchers and those within the military and Department of Veterans Affairs have studied a list of possible causes of GWI, ranging from stress, vaccinations, and burning oil wells to exposure to pesticides, nerve gas, anti-nerve gas medication, and depleted uranium.
Over the years, these studies have identified statistical associations with several of these, but no cause has been widely accepted. Most recently, Dr. Haley and a colleague reported a large study testing veterans’ urine for depleted uranium that would still be present if it had caused GWI and found none.
“As far back as 1995, when we first defined Gulf War illness, the evidence was pointing toward nerve agent exposure, but it has taken many years to build an irrefutable case,” said Dr. Haley, who holds the U.S. Armed Forces Veterans Distinguished Chair for Medical Research, Honoring Robert Haley, M.D., and America’s Gulf War Veterans.
Sarin is a toxic man-made nerve agent, first developed as a pesticide, that has been used in chemical warfare; its production was banned in 1997. When people are exposed to either the liquid or gas form, sarin enters the body through the skin or breathing and attacks the nervous system. High-level sarin often results in death, but studies on survivors have revealed that lower-level sarin exposure can lead to long-term impairment of brain function. The U.S. military has confirmed that chemical agents, including sarin, were detected in Iraq during the Gulf War. In particular, satellite imagery documented a large debris cloud rising from an Iraqi chemical weapons storage site bombed by U.S. and coalition aircraft and transiting over U.S. ground troop positions where it set off thousands of nerve gas alarms and was confirmed to contain sarin.
Previous studies have found an association between Gulf War veterans who self-reported exposure to sarin and GWI symptoms. However, critics have raised questions of recall bias, including whether veterans with GWI are simply more likely to remember and report exposure due to their assumption that it may be linked to their illness. “What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data,” Dr. Haley said.
In the new paper, Dr. Haley and his colleagues studied 508 deployed veterans with GWI and 508 deployed veterans who did not develop any GWI symptoms, all randomly selected from more than 8,000 representative Gulf War-era veterans who completed the U.S. Military Health Survey. They not only gauged sarin exposure – by asking whether the veterans had heard chemical nerve gas alarms sound during their deployment – but also collected blood and DNA samples from each veteran
The researchers tested the samples for variants of a gene called PON1. There are two versions of PON1: the Q variant generates a blood enzyme that efficiently breaks down sarin while the R variant helps the body break down other chemicals but is not efficient at destroying sarin. Everyone carries two copies of PON1, giving them either a QQ, RR or QR genotype.
For Gulf War veterans with the QQ genotype, hearing nerve agent alarms – a proxy for chemical exposure – raised their chance of developing GWI by 3.75 times. For those with the QR genotype, the alarms raised their chance of GWI by 4.43 times. And for those with two copies of the R gene, inefficient at breaking down sarin, the chance of GWI increased by 8.91 times. Those soldiers with both the RR genotype and low-level sarin exposure were over seven times more likely to get GWI due to the interaction per se, over and above the increase in risk from both risk factors acting alone. For genetic epidemiologists, this number leads to a high degree of confidence that sarin is a causative agent of GWI.
“Your risk is going up step by step depending on your genotype, because those genes are mediating how well your body inactivates sarin,” said Dr. Haley. “It doesn’t mean you can’t get Gulf War illness if you have the QQ genotype, because even the highest-level genetic protection can be overwhelmed by higher intensity exposure.”
This kind of strong gene-environment interaction is considered a gold standard for showing that an illness like GWI was caused by a particular environmental toxic exposure, he added. The research doesn’t rule out that other chemical exposures could be responsible for a small number of cases of Gulf War illness. However, Dr. Haley and his team carried out additional genetic analyses on the new data, testing other factors that could be related, and found no other contributing causes.
“There’s no other risk factor coming anywhere close to having this level of causal evidence for Gulf War illness,” said Dr. Haley.
The team is continuing research on how GWI impacts the body, particularly the immune system, whether any of its effects are reversible, and whether there are biomarkers to detect prior sarin exposure or GWI.
“Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample” by Robert W. Haley, Gerald Kramer, Junhui Xiao, Jill A. Dever and John F. Teiber, 11 May 2022, Environmental Health Perspectives.
“Invited Perspective: Causal Implications of Gene by Environment Studies Applied to Gulf War Illness” Marc G. Weisskopf and Kimberly A. Sullivan, 11 May 2022, Environmental Health Perspectives.
Other UTSW researchers who contributed to this study include John Teiber, Gerald Kramer, and Junhui Xiao. The U.S. Military Health Survey was a collaborative effort of UTSW and a large survey research team at RTI International including Jill Dever, who also contributed to this paper. The study was funded by the U.S. Departments of Defense and Veterans Affairs. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Departments of Defense or Veterans Affairs.
“The Americans at Château-Thierry” by N.C. Wyeth
The U.S. military has been actively working to remove references to the Confederacy and Confederate leaders in recent years, but that hasn’t always been the case. Just over 50 years after the end of the Civil War, parts of the United States still embraced that troubled past.
By the time the United States entered World War I, veterans from both sides of the Civil War were largely elderly. An 18-year-old who enlisted in 1861 would be 74 years old in 1917, the year the U.S. entered the Great War.
Even so, the U.S. Army wanted to bring something uniquely American to the trenches of Europe. The commander of a particular southern Army unit wanted his men to use the Confederate Rebel Yell to “instill terror in the hearts of the enemy.” And they needed the help of Confederate Civil War veterans to do it.
Fort Gordon near Atlanta, Georgia, (named for a Confederate general) was known as Camp Gordon during the build up to World War I. It was used as a training camp for many of the 2.8 million men who were drafted to serve in the war.
It was first opened in July 1917 and became the training ground for the 82nd Division, later known as the 82nd Airborne Division, when troopers could actually become airborne. The camp operated from 1917 until 1919 and trained many of the conscripts from Georgia.
The man installed to oversee the training of the 82nd Division at Camp Gordon was Gen. Eben Swift, a veteran of the Spanish-American War and the Pancho Villa Expedition and a former director of the Army War College.
Swift wanted to give the Germans a special surprise when the U.S. Army arrived and began fighting in the trenches. He wanted to teach the 82nd Division the “Rebel Yell,” a battle cry used by Confederate soldiers as they charged Union lines during the Civil War.
He met with federal judge William T. Newman of Atlanta, a former Confederate soldier who was still in contact with a company of his fellow veterans in Georgia, to teach the battle cry to new soldiers of the 82nd.
“I want my men taught the Rebel Yell for their use in France,” Swift told the Times-Dispatch, a Richmond, Virginia, newspaper in 1917. “I met Judge Newman and suggested the Rebel Yell would not sound badly when we meet the Germans. Our boys will use it when they go over the top.”
Although there aren’t any recordings of the yell in use during the Civil War era, there are recordings of Confederate veterans performing the cry at reunions years later. The video below is from Smithsonian Magazine:
According to the article, Newman did everything he could to assemble the elderly veterans at Camp Gordon to teach the troops the “blood-stirring” battle cry. Union veterans have remarked that the Rebel Yell was effective on the battlefield, saying “if you claim you heard it and weren’t scared, that means you never heard it.”
Swift expected the use of the Rebel Yell to catch on in the Army once the 82nd began using it, and that the service would adopt the Confederate tradition for the foreseeable future. Instead, it died out with the last of the Confederacy’s remaining veterans.
The new guns and ammunition the Army just married and is expected to issue to combat arms units within the next decade will require soldiers to carry an even heavier load.
But information on how those weapons should outperform the guns they’re replacing — the justification for troops to shoulder extra weight on top of mountains of gear already injuring soldiers — is classified.
In April, the Army announced that Sig Sauer will produce replacements for the M4 rifle and M249 Squad Automatic Weapon, or SAW, starting with a trial run of about 40 new guns late next year. Production is expected to ramp up when the Army opens a new ammo plant to produce the new 6.8mm rounds for those weapons around 2026.
Army officials have touted that the new XM5, the M4’s replacement, and XM250, set to replace the SAW, pack a much harder punch and will improve the combat performance of ground troops. But thus far, the service has declined to disclose evidence that those weapons outperform the M4 and SAW, including how far they can shoot accurately. And it’s unclear whether the Army has verified the ranges at which those new weapons can engage an enemy before committing to a multimillion-dollar contract.
“During the prototyping phase of the program, the [weapons] demonstrated the ability to significantly outperform the M4A1 and M249 with lethal effects at all ranges,” Lt. Col. Brandon Kelley said in a statement. “Following production qualification testing and operational testing, the Army will establish and validate the maximum effective ranges.”
Prototyping and the Army’s selection of which vendor would supply its new weapons took only 27 months. For comparison, the service spent more than a decade developing its new fitness test.
A spokesperson for Sig Sauer declined to comment, directing Military.com to the Defense Department regarding questions on its weapons.
Information on the maximum distances other Army weapons can engage targets is no secret; it’s one of the first things a new recruit learns and is easily searchable online. According to Kelley, the new weapons’ capabilities eventually will be disclosed, but there is no clear timetable.
The M4, the Army’s current standard-issue rifle used in the post-9/11 wars, can effectively engage targets at 500 meters. The SAW can suppress targets at around 800 meters.
For comparison, the standard-issue rifle for the Chinese military is the QBZ-95, which has a maximum effective range of 400 meters for a target.
Those distances are critical for troops to be able to confront an enemy force accurately, and anything less could alter U.S. soldiers’ effectiveness and even require changes to tactics. An Army report in 2009 on U.S. troops’ performance in ground combat in Afghanistan found that the average gunfight was well beyond 300 meters and that any training or equipment not built for at least 500 meters would be “inappropriate.”
But holding those details close to the chest before weapons are distributed to the force might be done out of fear of the Chinese government getting a sneak peek at the new guns.
“You don’t want the Chinese getting it,” Kelley told Military.com. “They steal tech all the time. Let’s get ahead while we can.”
The plan is for the new weapons to be issued only to troops in combat arms units, such as infantrymen and cavalry scouts. The Army plans to buy 107,000 XM5s and 13,000 XM250s for active-duty soldiers and National Guardsmen. But that total purchase could take the rest of the decade. Eventually, the XM5 will be renamed the M5, and the XM250 will be designated the M250.
Yet when soldiers eventually get those new guns, they will carry significantly less ammunition, given the 6.8mm is much heavier than the 5.56mm rounds the M4 and SAW use. The idea is those heavier rounds will be more effective against body armor and light vehicles. However, the Army has not disclosed any evidence on that being the case.
The XM5 weighs 8.38 pounds, or 9.84 pounds with the suppressor, much heavier than the 6.34-pound M4. That new rifle will also use 20-round magazines, smaller than the 30-round magazines troops currently use. A soldier’s basic combat load will be seven of those 20-round magazines, a total of 140 rounds, weighing 9.8 pounds altogether.
The M4’s combat load, also seven magazines for a total of 210 rounds, is 7.4 pounds. In total, a rifleman with the XM5 will carry roughly four pounds more than today’s M4 rifleman.
“Hopefully, these are worth the bang for the buck,” one Army infantry sergeant major told Military.com on the condition of anonymity because they were not authorized to talk to the press on the subject. “Asking [soldiers] to carry anything more than they already do, and having less ammo, that is a hard pitch.”
How ground troops pack is meticulously planned, with even an extra single ounce taken into account as their total load has ballooned in recent decades. Soldiers often carry between 30 and 80 pounds, or possibly more depending on the mission, lugging around batteries, radios, water, food, protective gear and grenades.
“Soldiers will carry less ammunition, but the performance of that ammunition provides an increase in lethality, accuracy and range across a broader range of targets,” Kelley added in a statement.
The XM250, however, weighs less, at 14.5 pounds, than the SAW, which weighs 19.2 pounds. That XM250 weight includes its bipod and suppressor.
But like the new rifle, light machine gunners will still carry that heavier 6.8mm ammo, and less of it. That could be a challenge, given a SAW gunner’s job is to fire a lot of rounds, quickly, to suppress enemy movement.
A soldier with an XM250 will carry a basic load of four 100-round pouches of ammo, weighing 27.1 pounds. SAW gunners carry three, 200-round pouches, weighing 20.8 pounds.
In total, future light machine gunners will carry 200 fewer rounds of ammunition and about one extra pound when accounting for the weapon and its ammo. It is unclear what the spare barrels for the XM250 weigh.