The Fog of War
The doctor examined the fresh wound and shook his head. The bullet had pierced the soldier's right thigh, pulverizing his femur before exiting the back of the leg, leaving behind a bloody mess. It would soon become infected, and the physician, a captain in England's Royal Army Medical Corps, closed his large blue eyes and imagined what was to come. There was no shortage of terrible fates befalling soldiers with this kind of injury, from amputation to gangrene, even organ failure. But he was most worried about tetanus-a lethal condition causing paralysis and eventual suffocation-that was terrorizing so many British soldiers in his battlefield hospital on the Western Front.
It was October 24, 1914, and Alexander Fleming, a thirty-four-year-old doctor from Scotland, was caring for a throng of men at a makeshift military base in Boulogne, France, that doubled as a wound-research laboratory. The Great War was just eleven weeks old, and already losses were heavy. British soldiers had arrived in France on August 7; two weeks later, French and British infantry were brutally defeated by the Imperial German Army in a forest fight at the Battle of Ardennes. The unexpected drubbing had triggered a slow and humiliating retreat as the Germans continued their march toward the French capital.
Then, on September 6, something astonishing had happened: thirty miles northeast of Paris, six French field armies and the British Expeditionary Force suddenly halted and counterattacked. For three gruesome days, the battle shifted back and forth along a one-hundred-mile front. Owing to remarkable advances in artillery-powerful new machine guns, howitzers, and mortars-it was one of the bloodiest engagements in the history of warfare.
The Allies' gambit worked. Devastating losses forced the Germans to abandon plans to invade Paris. The victory, however, came at an extraordinary cost: more than two hundred thousand French and British soldiers were wounded at what would become known as the first Battle of the Marne. In its aftermath, waves of injured men, bathed in blood and riddled with shrapnel, were brought to Fleming's hospital.
The young doctor grabbed a damp cloth from his surgical bucket and dabbed the soldier's leg, cleaning mud, blood clots, and shreds of uniform from the gaping exit wound. He picked up a scalpel and carefully excised a small swatch of fabric from the man's muddy pant leg. This piece of clothing, Fleming hoped, would solve one of the most puzzling questions of World War I: Why were so many soldiers dying of tetanus?
It was a rare disease, typically infecting only one in every hundred thousand people, but in Boulogne it was everywhere. Fleming suspected that the bacteria causing tetanus was embedded in British military uniforms. When soldiers were shot, he reasoned, the organism was introduced into the bloodstream, overwhelming the body's defenses. Fleming rushed to his laboratory, handling the scrap of dirty clothing with great care. He passed row after row of camp beds holding injured soldiers from Marne, and Mons and Ypres in Belgium. Many had lain on the battlefields for days.
The makeshift laboratory was located in the musty basement of an old casino, beneath high-ceilinged, ornate, once-elegant rooms, and it was covered with signs of Fleming's ingenuity: incubators he'd heated with paraffin stoves, Bunsen burners running on alcohol, glass-blowing burners using fire bellows, and a matrix of petrol cans and pumps to supply water. At his lab bench, Fleming squeezed the small piece of fabric into an empty test tube and placed it next to a row of tubes that were all incubating clothing from injured soldiers. After adding a special broth to the glass, Fleming returned to his patient and went about the task of dousing the man's thigh with antiseptic fluid.
Peering closely into the wound, Fleming could imagine how this would play out: For the next few days, discharge from the leg would be reddish-brown and foul smelling, consisting mostly of clotted blood and bacteria. After a week, the dank material would lose its pigment and odor, gradually transforming into a thick soup of pus. If the soldier was unlucky, as many Brits in France were, he would develop fever, restlessness, irritability, palpitations, and, finally, the telltale sign of tetanus: lockjaw. Tetanus caused facial spasms that left many soldiers with a permanent grin-a perverse condition called risus sardonicus-before inducing paralysis and an agonizing, slow death.
The bacterium responsible was a common inhabitant of horse intestines, and its spores-the reproductive units-could lie dormant for years in soil containing traces of manure. Tetanus was an anaerobic organism, which meant it did not grow in the presence of oxygen. Even brief exposure was enough to kill it. So why was it flourishing on the well-tilled fields of Belgium's Flanders region, where oxygen exposure was constant? And, more importantly, in wounds exposed to air? Fleming thought that the bacteria were hiding out under shrapnel, within the recesses of the wound, where oxygen was scarce and antiseptics were washed away by the discharge of pus. That was why the harsh chemicals that easily killed tetanus in a test tube failed to do so in flesh.
Fleming had come to France at the behest of his mentor, Almroth Wright, a controversial figure who had been the first to mass-produce a vaccine against typhoid fever. In contrast with Fleming, who, owing to his small stature, was often asked to play women in his dramatic society-he took on the role of a vivacious French widow in a production of Arthur W. Pinero's comedy The Rocket-Wright was a bear of a man, with a bushy brown mustache, small spectacles, and lock of wavy hair parted fiercely to the right. Some suspected he suffered from a hormonal disorder. They, too, made for an unusual pair.
Wright had lobbied hard for his typhoid vaccine to be given to British troops during the war, and when there was some initial hesitation-routine vaccination was not yet en vogue-Wright published an impassioned plea in the London Times, "On the Inoculation of Troops Against Typhoid Fever and Septic Infection." The piece had appeared four weeks earlier, on September 28, 1914, just seven weeks after Britain had declared war on Germany in response to its invasion of France. Although the public appeal was unpopular with many doctors-some of whom referred to him as "Almost Wright"-it worked, and the British army quickly made vaccination against typhoid compulsory.
Wright had also recommended vaccination against sepsis, but the director general of the British Army Medical Service, Sir Alfred Keogh, was unconvinced. He suggested more research was needed before mandating a second inoculation. Wright created a wartime research unit to study the bacteriology of wound infection, and this was where Fleming now found himself.
Surrounded by infection, unable to help the thousands of men who were suffering and dying around him, Fleming had become consumed by a desire to discover something that would save his soldiers. But at the moment, he had only antiseptic fluid, wound dressings, an untested antitoxin generated from horse blood, and his scalpel, none of which could protect them from a bacterium that was proving remarkably hard to kill. For some of his infected men, the cure would involve a hacksaw.
The medical world in which Alexander Fleming toiled as he shuttled between injured soldiers and his casino laboratory was defined by two approaches to the treatment of infected wounds: the physiological school, which concentrated its efforts in aiding the natural protective agencies of the body against infection, and the antiseptic school, which aimed at killing the microbes in the wound with a chemical agent. Fleming knew antiseptics worked well in theory, but he worried that the active ingredients-caustic chemicals such as boric acid, flavine, and carbolic acid-might actually be harming his patients. The soldiers simply didn't get better with antiseptics, and the doctor had a hunch that they might in fact allow the tetanus bacterium to proliferate.
His theory was that abrasive chemicals might work in the central cavity of the wound, but they lacked the penetrative power to clean the tissue at the edges. Something about the periphery allowed bacteria to thrive. It was a radical thought, one that would have had Fleming laughed out of any hospital in Europe, but he was increasingly certain that antiseptics were killing his men, and he was designing an elegant experiment to prove it-one that drew on his life before medicine.
Prior to enrolling at St. Mary's Hospital Medical School in Central London in 1903, Alexander Fleming had learned an odd craft: glassblowing. Mostly he made tiny figurines-glass cats and scampering mice for family and friends-but when resources were scarce, he made his own research equipment, including test tubes. In Boulogne, Fleming began dreaming of ways to design tubes with contours that would approximate the jagged dimensions and texture of a bullet wound. The experiment was still in its infancy, but if it worked, it would turn the treatment of combat wounds on its head. Antiseptics were central to medical care during the Great War; British military policy mandated their use. Fleming was convinced they were not simply useless, they were dangerous.
But Little Flem, as he was known, was not drawn to controversy, or to combat, or even to conversation. (One colleague claimed that trying to speak with him was like playing tennis with a man who, when he received a serve, put the ball in his pocket.) The doctor knew he had a story to tell; he just had to write it.
More than seventeen million military personnel died during World War I, many of them from tetanus. After the fighting was over, Fleming returned to London and to his lab bench in the Inoculation Department at St. MaryÕs Hospital. By the time the armistice was signed on November 11, 1918, Fleming had published a dozen papers based on his work at Boulogne, and he was known in academic circles for his ingenious experiments with glassware. But he was a lone voice, and antiseptics still ruled the day.
Haunted by what he had seen on the Western Front, the young doctor spent the next decade in his laboratory, just up Praed Street from Paddington Station, trying to devise ways to destroy harmful bacteria and improve the treatment of infections. It was tedious work, staring at thousands of bacterial colonies in petri dishes in a dimly lit laboratory day after day, but it fulfilled him. He was consumed by a desire to understand how bacteria thrived and, more importantly, how they could be killed.
A chance observation in September 1928, a decade after the war, was briefly cause for celebration. One afternoon, Fleming noticed that the Staphylococcus bacterium-one of the pesky organisms that was so prevalent in battlefield wounds-was killed in the presence of a fungus called Penicillium rubrum. This accidental finding occurred in a discarded petri dish and led to the discovery of what he called a slow-acting antiseptic. Fleming dubbed it penicillin.
On May 10, 1929, he sent his findings to the British Journal of Experimental Pathology. Fleming wrote: "Penicillin . . . appears to have some advantages over the well-known chemical antiseptics. . . . If applied, therefore, on a dressing, it will still be effective even when diluted 800 times, which is more than can be said of the chemical antiseptics in use." The utility of this finding, however, was not yet clear. Penicillin could kill bacteria in petri dishes and test tubes, but it failed in the presence of blood. Because the fungus took several hours to exert its effect, Fleming was resigned to the fact that while penicillin might work superficially, it would be destroyed in the human body before it could ever kill the bacteria in a festering wound. Penicillin wouldn't save injured soldiers or anyone else. Instead, he thought it would serve as a valuable tool for preventing Staph bacteria from contaminating laboratory experiments.
Fleming was not the first scientist to notice that microorganisms could kill bacteria. Others had similarly suspected that their fungal extracts were either too feeble or too toxic to treat human bacterial infections, and they were discarded into the dustbin of history. They simply didn't realize they were on the precipice of something that would alter the course of human health forever.
Regrettably, Fleming's penicillin paper was not written in a way to make his findings accessible or reproducible. It was as if the manuscript had been dashed off in midthought. He did not explain how the molecule was purified from the fungus or where one might gain access to his chemical reagents to replicate his work. And he was such a poor public speaker that his lectures did little to inspire colleagues. To make matters worse, Fleming's collaborator had misidentified his fungus: it was Penicillium notatum, not Penicillium rubrum. Anyone hoping to reproduce his experiment was out of luck.
Investigators at Oxford University and Sheffield University Medical School, however, agreed with Fleming's assessment that because it killed off laboratory contaminants, penicillin could be useful to isolate and study a bacterium called Bacillus influenzae (now called Haemophilus influenzae), which some thought was responsible for the influenza pandemic of 1918. The outbreak had begun in Spain in May of that year, as World War I was coming to a close, and toward the end of Fleming's deployment, cases of influenza at his French hospital far outnumbered the wounded. By 1919, twenty million people had died from the infection, and the urgent need for some understanding kept Fleming's fungal research going. Still, they believed that penicillin was crucial only for studying influenza-no one, not even Fleming himself, realized that he had stumbled upon a rare strain of fungus that produced penicillin at such an extraordinary level that it could be used to treat human infections. By the summer of 1929, just a year after its discovery, he abandoned work on the penicillin molecule. It would be more than a decade, and another world war, before Fleming and colleagues at Oxford would revisit it, teaming up with the burgeoning pharmaceutical industry to create the world's first mass-produced, commercially available antibiotic.