Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (18 page)

Hastily formed rescue squads pulled more than a thousand men from the oily bitter-cold water. These survivors were wrapped in blankets and laid out in rows of stretchers on the ground in improvised dressing stations. Many suffered from burns and were in various stages of shock. Hospital personnel handled the influx of casualties as best they could. With the onrush, there was no time to remove the oil-soaked clothes from the survivors, wash their bodies clean of the slime, and provide them with fresh gowns or new uniforms. They were kept wrapped in blankets for as long as twenty-four hours.

Soon many began showing new symptoms: stinging eyes, excessive tearing, and eyelid spasms that led to difficulty in seeing. Areas of the skin showed brawny edema, painless at first; later, superficial layers of skin peeled off in sheets. Most striking was the puzzling nature of the shock in some of the patients. Even though their pulses were weak and their blood pressure extremely low, they did not present the typical picture of shock and showed no response to the usual measures. The doctors were struck by a consistent apathy in these men. In a not unusual instance, a patient would state that he felt rather well, even though his pulse was barely perceptible and his blood pressure very low; then he would promptly and quietly die.

Four survivors died the first day, nine the next, eleven on the third day. A few individuals who had been well enough to clean themselves of the oil and perhaps change their uniforms saved their lives by these simple acts. By the end of a month, eighty-three men had died. Since many of the survivors had severe eye irritations, it was strongly suspected that the German aircraft had used chemical bombs.

Lieutenant Colonel Stewart Alexander, a twenty-nine-year-old medical officer trained in chemical warfare and then on the staff of General Dwight D. Eisenhower's Allied Force Headquarters in Algeria,
was dispatched to Bari on December 7 to investigate. Upon entering the hospital ward in Bari, he was immediately struck by an unexpected smell. Was it, of all things, garlic? Then he remembered he had encountered the same odor two years earlier when he had undertaken research on the effects of mustard gas.

Upon examining the patients, he first noticed unusual skin lesions. Their distribution confirmed Alexander's notion that a chemical toxin had touched the victims’ skin. The burns clearly followed the pattern of exposure to the oily slime on the surface of the harbor. Men who had been immersed in the oil solution and then wrapped with a blanket suffered burns all over their bodies. If only the legs or arms had been exposed, burns were restricted to these parts. If a survivor had been splashed by the oily water from the harbor, the affected areas had first- and second-degree burns. Blister tracks could be traced on the chest or back where contaminated water had trickled down. Those engulfed by the black clouds of smoke had vapor burns on their exposed skin and in their armpits and groins.

Alexander speculated that if the chemical agent had been liquid mustard, it would have been diluted by the seawater, and the concentration in the different areas of the harbor would have varied considerably. Diluted mustard would cause different symptoms than those caused by concentrated mustard.

In Alexander's attempt to get to the bottom of what had happened, two things conspired to mislead him: British port authorities denied that any ship in the harbor had been carrying a chemical agent. And on the third or fourth day after the air strike, a bomb casing containing mustard that was recovered from the bottom of the harbor was assumed to be German.

Alexander was relentless in trying to determine exactly what had happened. He reviewed the manifests of the ships, searching for the type of cargo that might indicate the delivery system for mustard, and ordered chemical analysis of an oil sample from the harbor, autopsies with tissue samples, and a sketch of the harbor showing the anchorage of the ships. The autopsies confirmed chemical as well as thermal burns of the skin and toxic vapor injury of the lungs.

The sketch was crucial in correlating the hospital deaths with the
ship positions, showing that the greatest number of mustard-induced deaths occurred among the personnel closest to the
John Harvey.
Another break resulted from the discovery that the recovered bomb casing was American, not German. Finally, the British port officials admitted that the
John Harvey,
which had been in the center of the moored vessels, had been carrying 100 tons of mustard gas! Not one member of its crew survived. The port authorities blundered terribly in failing to notify the struggling medical staffs in the overcrowded hospitals of the gas disaster. Colonel Alexander had been forced to uncover the hidden existence of the mustard gas step by step.

Gas warfare had been outlawed in 1925 by the Geneva Protocol. Nevertheless, before the actual outbreak of World War II, U.S. Secret Service information indicated that both the Germans and the Japanese were preparing to use poison gas.
²
In response to ominous reports that Hitler planned to resort to the use of poison gas against any invasion of southern Europe, President Franklin Delano Roosevelt announced Allied policy regarding this in August 1943. After decrying such inhumane weapons, Roosevelt warned that the United States would undertake “full and swift retaliation in kind…. Any use of poison gas by any Axis power, therefore, will immediately be followed by the fullest retaliation upon munition centers, seaports, and other military objectives throughout the whole extent of the territory of such Axis country.” Consequently, mustard gas was stored at various depots in combat areas around the globe for reprisal use.

Chemical warfare had been notoriously introduced by the Germans during World War I. On April 22, 1915, they released a lethal cloud of chlorine gas on the French lines at Ypres in Flanders. The gas caused death by stimulating overproduction of fluid in the lungs, leading to drowning. By 1917 they had developed and employed, also at Ypres, a new diabolically efficient blistering agent and systemic poison, dichloroethyl sulfide. Called “yellow cross” because of its shell marking, it was fired at the enemy by artillery. The oily brown liquid evaporated slowly, remaining effective for several hours to several days. The heavier-than-air vapor sank into the trenches and lingered as a poison cloud. No mask provided protection against it. It burned through clothing, blistered the skin, destroyed vision, and choked out life.

The poison agent was also given other names. To commemorate the site where it was introduced, some termed it Yperite, but the most common name given to the chemical that has come down to us is “mustard gas,” based on its smell, which resembles that of garlic or mustard in high concentration.
⁴

It has been estimated that more than 9 million shells filled with mustard gas were fired by both sides during World War I, causing some 400,000 casualties. Among these, the fatality rate was very low, 2.2 to 2.6 percent, with death most often due to pneumonia.

Immediately after the Bari air raid, more than 800 men were hospitalized. Later it was discovered that 617 of the injured were suffering from mustard exposure. Of these, 83 died. This fatality rate of more than 13 percent was much higher than the rate encountered in World War I. It was obvious that most of the deaths were due principally to the men's exposure for prolonged periods, which was unlike the experience in the earlier war. In this case, men were literally saturated with the lethal solution. The dilution of the mustard gas in the oil-soaked surface of the water and its slow absorption over the ensuing hours caused medical effects that had not been previously encountered.

In his report dated June 20, 1944, Alexander emphasized that the “systemic effects were severe and of greater significance than has been associated with mustard burns in the past.” A conspicuous feature had been the
overwhelming destruction of white blood cells.
Beginning on the third or fourth day, there was a critical drop in one type of cell—the lymphocytes—after which the rest of the white blood cells disappeared.
⁵
In lymphomas and leukemias, there is an overproduction of white blood cells by the diseased bone marrow. Alexander's observations suggested at once the significance of mustard compounds for the possible treatment of cancers of the tissues that form white blood cells.

Meanwhile, important advances were being made on the home front. At Yale University, secret wartime research on the toxic effects of mustard exposure had been undertaken, and the huge set of medical data—including tissue blocks from the Bari disaster—provided crucial information. In 1942 the U.S. government's Office of Scientific
Research and Development had contracted with Yale to do research directed toward the treatment of gas casualties.

Colonel Cornelius P. Rhoads, on leave from the directorship of Memorial Hospital in New York City, was the chief of the Medical Division of the Army Chemical Warfare Service. With keen insight, he recognized from Alexander's report the opportunity to further investigate the use of chemical agents against cancer. Rhoads was a pathologist with particular experience in hematology, or blood disorders. Drs. Alfred Gilman and Louis S. Goodman,
⁶
pharmacologists at Yale, were assigned to the study of systemic effects of mustard gas in animals in order to develop a suitable antidote. They looked at modified mustard compounds and centered their research on a group known as nitrogen mustards. They learned how the mustard compounds change in the body through a series of chemical transformations.
⁷
Their studies underscored the remarkable sensitivity of normal lymphoid tissue to the lethal action of the nitrogen mustards. “The clinical observations on the casualities of the Bari disaster,” Rhoads declared, “illustrate as adequately as any example can, the effects of the mustard compounds on blood formation.”

Impressed by the way in which white blood cells were consistently depleted whenever a subject was exposed to mustard for a period of time, they speculated how this toxic effect could be used to advantage. To these investigators, thinking creatively was a natural reflex. It required the mental formulation “I have a solution! What is the problem?” Perhaps nitrogen mustard could be used as a new approach to battling cancer, for which surgery and radiation were then the only effective therapies. So they turned to their colleague Thomas Dougherty in the Department of Anatomy and suggested that he conduct experiments on mice. As they put it, “The problem was fundamental and simple: could one destroy a tumor with this group of cytotoxic agents before destroying the host?”
⁸

T
HE
M
OUSE
T
HAT
R
OARED

Dougherty used doses of nitrogen mustard in a mouse in which he had transplanted a lymphoma (tumor of lymphoid tissue) that was expected
to kill the animal within three weeks of transplantation. The tumor was so advanced that its size almost dwarfed that of the mouse. After two doses, the tumor began to soften and shrink. Eventually it disappeared, and the mouse became frisky. “This was quite a surprising event,” Dougherty exclaimed.

A recurrence regressed under further doses, but another recurrence did not, and the animal died eighty-four days after transplantation. Astonishingly, this unprecedented prolongation of life was never matched in later studies on a large group of mice bearing a variety of transplanted tumors, although good remissions were frequently obtained. Years later, Dougherty reflected on this singular incident: “The very first mouse treated turned out to give the best result…. I have often thought that if we had by accident chosen one of these leukemias in which there was absolutely no therapeutic effect, we might possibly have dropped the whole project.”
⁹
Fortunately, this was the mouse that roared.

In December 1942 a therapeutic trial with intravenous nitrogen mustard was undertaken by the Yale group in a forty-eight-year-old silversmith in the terminal stages of a highly malignant lymphoma that had become resistant to radiation. Massive enlargement of multiple lymph nodes throughout his body was causing dire symptoms: those in his face and neck made chewing and swallowing impossible; those in his armpits made him unable to bring his arms down to the side; and those within his chest blocked the return of blood to his heart, causing his head and neck to swell. The patient's response to the treatment was dramatic. The bulky tumor masses receded. But the disease eventually recurred and the man died. Five other patients in the terminal stages of a variety of malignant diseases were subsequently treated at Yale, with poor results.

The drug had the Merck trade name Mustargen but was identified as Compound X in hospital charts. Nitrogen mustards were still classified as “top secret,” and investigators were sensitive to the view at the time that “in the minds of most physicians, the administration of drugs, other than analgesic, in the treatment of malignant disease was the act of a charlatan.”
¹⁰
Between 1943 and 1946, several medical institutions carried out controlled clinical studies under a mantle of
military secrecy. The multicenter trial established a pattern for future research to determine the effectiveness of different treatment protocols by accumulating enough patient data. Restrictions on publication of data were finally removed, and two major reports came out in 1946. Alfred Gilman published the first review in the open literature of the classified wartime investigations,
¹¹
and Cornelius Rhoads, as chairman of the Committee of Growth of the National Research Council, summarized the results of treatment of cancers with nitrogen mustard in a multicenter study of 160 patients, emphasizing their therapeutic value in cancers of the white-blood-cell-forming tissues.
¹²
Other reports of clinical investigations conducted during the war years were also released.