From Poison Gas To Wonder Drug
Chemotherapy was born in a chemical-weapons laboratory.
IN THE EARLY 1940S A DIAGNOSIS OF CANCER WAS USUALLY a death sentence, with a small chance of a reprieve and the certainty of great suffering beforehand. Some doctors would not even tell cancer patients that they had the disease. The only known cures were surgery, which required cutting out much extra tissue surrounding the tumor; radiation therapy, which worked only with certain forms of cancer and destroyed healthy cells along with cancerous ones; and hormone treatment, which was modestly effective in some cases but had distressing and occasionally permanent side effects. Together these methods managed to cure about one cancer patient in four.
Beyond the few accepted treatments lay a great variety of purported anticancer drugs, some of which seemed genuinely effective until they were tested and some of which were outright quackery. Among these were compounds with names like KR, teropterin, krebiozen, and colloidal lead; extracts of spleen, lemon, and the root of the May apple; and ultrasound and vitamin therapy. Drugs that were supposed to cure cancer—or any other intractable disease—had a poor reputation among mainstream physicians, and understandably so.
At the time, most drugs were palliatives like cough syrup, meant to lessen the severity of a disease’s symptoms while the body’s natural defenses did their work. To be sure, the previous century had seen medical triumphs against many deadly diseases. But these had all resulted from the spread of vaccination, improvements in sanitation and hygiene, and changes in diet. The only true curative drugs then in common use were arsphenamine, used to treat syphilis, and the antibacterial sulfonamides, or sulfa drugs, which had become available in the mid-1930s. Penicillin, the first true antibiotic, had just been discovered and was in very limited supply until late in World War II.
It is perhaps no surprise, then, that the first drug effective against cancer was developed not by an established scientist as part of a planned research program but by a pair of junior researchers who had been investigating something entirely different. That drug, now known as mechlorethamine, is still in use against leukemia, lymphoma, and certain solid tumors. It provides the M in MOPP, a cocktail of pharmaceuticals used against Hodgkin’s disease. But in early 1942, when the biochemist Alfred Gilman, the physician Louis Goodman, and their colleagues began studying this compound, they knew it as HN2, the top-secret code name for a lethal chemical weapon of the class known as nitrogen mustards. It was a close cousin of the mustard gas that had maimed and killed thousands in World War I.
Mustard gas caused appallingly dreadful injuries. Victims came to aid stations “burnt and blistered all over with great suppurating blisters, with blind eyes—sometimes temporarily, sometimes permanently—all sticky and stuck together, and always righting for breath,” reported Vera Brittain, a nurse who served on the Western Front. In an unwitting reference to a discovery that then lay 25 years in the future, the poet Wilfred Owen wrote that the blood that came “gargling from [the soldiers’] frothcorrupted lungs” was “obscene as cancer.”
The first successful use of poison gas in warfare—except for suffocating smoke, which dates to ancient times—came on April 22, 1915, at Ypres, Belgium. (The Germans had tried an unsuccessful gas attack on Russian troops in Poland three months earlier.) An eyewitness wrote that “a strange opaque cloud of greenish-yellow fumes” rose from the German line and wafted toward the French trenches. Men “fell gasping for breath in terrible agony.” The French forces broke in panic. Those who could flee did so; those who could not flee died where they lay.
The lethal fumes were chlorine gas, which turned to caustic hydrochloric and hypochlorous acids on contact with moist tissues. As the war progressed, the use of gas spread among both sides, at first in wind-borne clouds and later in gas-filled projectiles (something that the Union Army had considered and rejected during the Civil War). Phosgene, or carbonyl chloride, with a deceptively pleasant smell of new-mown hay, was also used. The combatant nations hurried to devise gas masks and decontamination facilities. Then on July 12, 1917, nearly three weeks before the third battle of Ypres (also known as Passchendaele), the Germans introduced an even more awful weapon.
Mustard gas, also known as sulfur mustard, not only choked and blinded its victims but caused the hideous burns and blisters Brittain described, as well as injuries to the respiratory and gastrointestinal systems. It was harder to neutralize than chlorine-based gases, and it persisted much longer in the air and on clothing and other surfaces. Mustard gas quickly became known as yprite or ypérite. By war’s end, chemical weapons had killed some 33,000 men, including 1,462 Americans, and injured as many as 690,000, including 71,345 Americans. Because the Russian army delayed in providing gas masks and protective gear, two-thirds of the dead and wounded were Russians (though recent research suggests that the Russian casualty figures may have been overstated).
The first mustard gas, known to chemists as bis(betachloroethyl) sulfide, was synthesized in 1854. It was named for the distinctive smell produced by an early production method. Scientists soon noted its power as a vesicant, or blistering agent. By 1886 it had been produced in a purer form as a clear, odorless, oily liquid, but the name mustard stuck. Animal experiments confirmed its effects on the eyes, skin, lungs, and other organs.
The Hague conventions of 1899 and 1907 banned all poisons as military weapons, yet that did not prevent the gasborne horrors of World War I. After the Armistice, development of poison gases died down, and the Geneva Protocol of 1925, which once again outlawed chemical weapons, pushed them even farther into the background. In the late 1930s, however, as fears of a new European conflict increased, research began once more in many nations.
The experience of World War I had shown that it was hard to gain a tactical advantage with poison gas against a technologically sophisticated opponent that also had poison gas. Instead it simply made war much more unpleasant for all concerned. The only large-scale military uses of poison gas since World War I have been against enemies lacking gas masks, often by colonial powers fighting indigenous peoples. (The Germans, of course, also used poison gas in their death camps.)
Still, the approach of war made poison-gas research necessary, both to build up an arsenal as a deterrent against enemy attacks and to assess the effects of various gases and devise countermeasures. Researchers concentrated mainly on the most immediate and obvious contact injuries, especially the terrible blistering and burning of the skin and the destruction of lung and other respiratory tissue. A few, however, probed more subtle, systemic effects.
One area of research was a new branch of the mustard-gas family, the nitrogen mustards, which were discovered with the synthesis in 1935 of tris(beta-chloroethyl) amine, which the Americans soon code-named HN3. Related compounds, including methyl bis(beta-chloroethyl) amine—code-named HN2—soon followed. This work, always highly secret, went on at civilian laboratories and at the Army’s Edgewood Arsenal in Maryland.
In early 1942 Yale University signed a contract with the Office of Scientific Research and Development to undertake a large chemical-weapons project. Gilman and Goodman were assigned to study the effects of nitrogen mustard and come up with protections or antidotes. This meant finding out in detail what the gas did to various kinds of cells and tissues.
The two men were well suited to their task. Louis Goodman, born in Portland, Oregon, in 1906, was a graduate of Reed College and the University of Oregon Medical School and had served his internship at Johns Hopkins Hospital in Baltimore. After that, he went to Yale to study pharmacology, the emerging science of how drugs interact with the body. There he became close friends with Alfred Gilman, a fellow pharmacology postdoc. Gilman, born in Bridgeport, Connecticut, in 1908, had entered Yale as a freshman and stayed on through his 1931 Ph.D. in physiological chemistry, the field now known as biochemistry. He had dreamed of getting a medical degree and pursuing a career in clinical research, but the Depression forced him instead to become a postdoctoral fellow, first in biochemistry and then in pharmacology.
In 1935 Gilman and Goodman began teaching pharmacology to Yale medical students. Frustrated by the available textbooks, they decided they could write something clearer and more useful themselves. Their innovative manuscript, The Pharmacological Basis of Therapeutics , combined a systemic analysis of how drugs worked in the body with the very latest scientific research. It was first published in 1941 and remains a leader in its field today. The task of supervising the five-year updates has fallen to Oilman’s son Alfred Goodman Gilman, who was born the year of the book’s publication. The younger Gilman shared the 1994 Nobel Prize in Physiology or Medicine and is, as a friend of his once pointed out, “probably the only person who was ever named after a textbook.”
Gilman and Goodman began their war work by investigating exactly how HN2 and another of the nitrogen mustards, HN3, killed. They were assisted by a biochemistry postdoc, Frederick S. Philips, and their colleague Roberta P. Allen. Animal experiments showed that as ghastly as nitrogen mustard’s external effects were, they did not usually cause death. To separate skin blistering and gross organ damage from cellular-level processes, the researchers switched to injecting a solution of hydrochloride salts of HN2 and HN3. “The jibes of our colleagues that the enemy did not intend to attack with hypodermic needles were ignored,” Gilman later wrote.
Further experiments showed that nitrogen mustard did widespread and ultimately fatal damage to the body’s internal systems. Bone marrow, blood cells, the lymph system, and the lining of the digestive organs showed particular vulnerability. This set nitrogen mustards apart from other classes of poison gases, such as phosgene, which attacked the tissues of the lung, or nerve gases, which blocked the functioning of a key nervous-system enzyme. Before long the team had come up with an antidote to the nitrogen mustards’ systemic effects: Thiosulfate, if present in sufficient levels in the bodily fluids, would protect the cells from destruction.
As they continued injecting their rabbits, the researchers were amazed at how efficiently nitrogen mustard killed lymph cells and white blood cells. Why did this happen? What did these types of cell have in common that made them so susceptible? Goodman and Gilman realized that both types of cell were among those that multiplied most rapidly. With this insight, the team made the connection and asked the question that would turn the deadly military weapon HN2 into the lifesaving drug mechlorethamine.
Cancer cells also multiply extremely fast. In fact, wild, uncontrolled growth is the disease’s hallmark. For reasons that are still not completely understood, cells that become malignant break free from the constraints that normally keep their growth under tight control and cease functioning as normal cells. Malignant cells then invade the body’s vital organs and, if not stopped, destroy them.
The researchers did not understand why the nitrogen mustards targeted cells that proliferate very fast. That question would remain unanswered for many years, until after the genetic revolution that resulted from the discovery of DNA. But it was plain that the compound somehow impeded, even halted, their rapid growth. If it did that to normal cells, the researchers wondered, would it have the same effect on malignant ones? Specifically, could it kill tumors? And could it do so before it killed the creature that hosted the tumors?
Goodman and Gilman didn’t know if their idea would work, and they had no experience with cancer research. They did, however, have a colleague in the anatomy department, Thomas Dougherty, who was experimenting on lymphomas, or cancers of the lymph system, in mice. Goodman and Gilman told Dougherty what they had learned from their experiments on rabbits and what they hoped to learn. He offered them his mice.
Strict scientific protocol called for testing the hypothesis on more than one subject at a time, but assembling and treating a group of subjects would have taken too long. The war was on, time was short, and cancer therapy was off the main line of their weapons research. After experimenting on healthy mice to discover safe doses, they began with a single mouse that had a sizable, wellestablished tumor.
After only two doses, the mouse’s tumor “began to soften and regress,” Dougherty recalled. As the doses continued, the tumor shrank until they could not feel it: “quite a surprising event … I remember how exciting the next couple of weeks were.” The researchers then stopped the treatment altogether and watched in amazement as the mouse seemed to remain tumor-free for more than a month.
Then the cancer began growing back. It was tiny at first, and a new round of doses shrank it again, but not as much as the first time. The tumor swelled once more, and it continued to grow despite further treatment. Still, by the time of the mouse’s death, it had lived for 84 days beyond the original introduction of the malignant material. That was four times the usual survival period. During those thrilling months, the researchers tried their revolutionary treatment on a number of other mice. Many, but not all, responded. They experimented with different sizes and numbers of doses and with different kinds of malignancy, testing their drug against leukemias as well as other forms of lymphoma.
The researchers had been fortunate, Dougherty recalled, for “the very first mouse [we] treated turned out to give the best result.” It was “the only one … in which we got complete regression.” No other animal enjoyed an 80-plus-day survival: “The best we did was some forty day prolongation,” which was significant but much less spectacular. And some of the leukemias did not improve at all. “I have often thought that if we had by accident chosen [for the first try] one of these leukemias, in which there was absolutely no therapeutic effect, we might possibly have dropped the whole project.”
Their results were good enough to encourage them to find out whether their drug could benefit humans as much as it did mice. To perform an experiment on a person, and a risky and unorthodox experiment at that, required not only a patient willing to undergo it but a physician prepared to oversee it. They showed their results to Dr. Gustav E. Lindskog of Yale’s department of surgery. He was impressed and agreed to the plan, a decision that took courage, imagination, and what Gilman called “great faith in his pharmacological colleagues.” To make the experiment even more bizarre, the identity of the material being tested was a military secret. Lindskog had to write in his patient’s chart, ”0.1 mg per kg [of body weight] compound X given intravenously.”
In December a man with a terminal lymphosarcoma that was completely invulnerable to X-ray treatment began a 10-day course of HN3. At the start of the chemotherapy he was hovering near death, his neck, chest, and one underarm clogged with large tumors, his face and chest swollen, his skin blue. He could neither chew nor swallow and could barely breathe. With what Gilman would later call “unwarranted confidence,” the team decided on a daily dosage and began treatment.
Once again luck was on their side, for “the response of the first patient was as dramatic as that of the first mouse.” Within 48 hours the tumors began to soften. Within four days the patient could breathe and swallow easily. Elated by this apparent success, the researchers forgot what they had learned from their work with mice and rushed to begin the same treatment on a second patient. The first man continued to improve, the tumors vanishing from his neck and underarm. But soon the researchers realized that starting the second patient so quickly had been, in Gilman’s words, “a serious error in judgment.”
Over the next few weeks, well after the second patient had finished his 10-day treatment, the first man’s white blood cell count began to drop drastically. It was clear that his bone marrow had been severely affected by the drug. Even worse, as his marrow gradually recovered, the tumors reappeared. A second round of injections produced only a temporary regression, and a third produced almost none.
The second patient, meanwhile, was suffering a similar bone marrow suppression and plunge in his white cell count, but without any compensating tumor response. The researchers sorely regretted that their “acumen on the duration of therapy left much to be desired.” Nonetheless, they now had evidence for their hunch that nitrogen mustard could kill cancer cells while leaving the patient alive, even if future trials would require a more cautious approach. Tests on five additional patients followed.
Meanwhile, at another chemical-weapons research center, the University of Chicago’s toxicology laboratory, a young physician named Leon Jacobson and a pathologist and medical student named Clarence Lushbaugh had made the same surmise about nitrogen mustard as had the Yale team. In early 1943, within months of the first Yale clinical trial, they, too, undertook a human experiment, even though “giving an extremely toxic but potentially therapeutically effective chemical to a patient for the first time” filled Jacobson with “deep concern.” (The different chemical-warfare research groups kept in contact by circulating reports and meeting when they could.)
After injecting the patient , a man with intractable lymphatic leukemia, Jacobson did not leave his side for 24 hours. Before 15 minutes had passed, severe nausea struck, and vomiting persisted for hours. Only after several more hours was the man able to drink. These side effects happened despite the Chicago group’s more conservative approach to dosage. When they repeated the treatment after two and then four days, the nausea and vomiting recurred. But the extremely elevated white blood count, which is the mark of leukemia, “came down, and the leukemia-infiltrated lymph nodes and spleen became smaller. The patient definitely had a remission,” Jacobson wrote. A second patient experienced a similar encouraging result with Hodgkin’s disease.
Back at Yale, by the spring of 1943 the handful of scientists who were aware of this highly secret work agreed that larger clinical trials were necessary. Neither the medical facilities nor the chemical-warfare laboratory at Yale could accommodate such trials, and the scientists had other wartime responsibilities to assume, so the team that had made the epochal discovery split up. In June Goodman left Yale for a year at the University of Vermont, after which he joined the faculty of the University of Utah Medical School. There he founded the department of pharmacology and coordinated clinical trials at his own and other institutions. At the same time as Goodman left Yale, Gilman went to Edgewood Arsenal as the medical section’s head of pharmacology, eventually attaining the rank of major. After the war he joined the medical faculty at Columbia University, moving to Albert Einstein College of Medicine in 1956, shortly after its opening.
No researcher working on nitrogen mustard questioned that its effect on lymph tissue and bone marrow was as powerful in humans as in animals. In fact, data showing this from World War I mustard-gas casualties had been published as early as 1919. But mere months after Gilman and Goodman had left Yale, a hideous natural experiment at the port of Bari, in southern Italy, proved that fact beyond any doubt. During a German raid on December 2, 1943, twenty Allied ships were wholly or partially destroyed. Sixteen of them sank, among them the SS John Harvey , a merchant freighter carrying munitions, which went down with all hands. Along with its load of conventional armaments, the ship held a topsecret cargo of 2,000 hundred-pound bombs filled with a mustard agent, probably nitrogen mustard. Much of it dissolved in the oil slick where survivors of the ruined ship were fighting for their lives.
Since no one knew of the presence of the gas, rescuers made no effort to clean it off the survivors, many of whom lay overnight wrapped in blankets over their oil- and mustarddrenched clothes. By morning medical workers had begun to suspect that something was wrong, as many of their patients had blisters and burns and complained of eye pain. Eventually word came to watch for victims of “blister gas,” but by the time the last sailor was treated, some had had it on their skin for as long as 24 hours. Ultimately 617 men were treated for mustard injuries, and 83 of them died. An Army investigator noted severe damage to the white blood cells of the exposed men. When autopsy surgeons examined the lymph nodes and bone marrow, they found nodes that were “very pale and without normal markings” and marrow that was pale pink instead of its normal red color.
Not Until after the war was over did the medical profession at large learn of the astounding new therapeutic possibilities opened up by wartime chemical-weapons research. By then, hundreds of patients had participated in secret clinical trials that showed nitrogen mustard to be effective in slowing a number of cancers. They also confirmed something that had been obvious to the Yale group from the time of the second mouse.
Before the experiments began, researchers had expected to find a general treatment for all types of cancer, or at least for all cancers of a particular type. Instead they found that some agents worked for some cancers in some patients, but not in others. Nowadays, with a much greater understanding of the processes involved, oncologists consider each type of cancer to be a different disease and appreciate that individual responses to chemotherapy drugs vary widely.
Moreover, chemotherapy also kills normal cells, especially those that constantly renew themselves, such as the ones in hair follicles, the lining of the digestive tract, and the immune system. This creates such drearily familiar side effects as hair loss, nausea, and suppression of the immune system. Another often deadly mechanism of the disease is that malignant cells from even small tumors can spread to other parts of the body, through the blood and lymph systems and by other means, and establish new colonies, called metastases.
In the years since Oilman and Goodman’s discovery, thousands of substances have been tested for anticancer action, and dozens of them have been developed into drugs. Chemotherapy remains a cornerstone of cancer therapy along with radiation and surgery, though surgeons now remove far less tissue surrounding a tumor than they did in the 1940s. Oncologists can employ an arsenal of chemotherapeutic agents to attack malignant cells in the original, or primary, tumor and in metastases in distant, often unknown parts of the body. Numerous clever methods are available to concentrate the action of the drug or radiation on cancerous cells and away from healthy ones, allowing more powerful doses with reduced side effects.
But as Gilman and Goodman observed in their original experiments, the effectiveness of chemotherapy drugs still varies among patients, for reasons not yet fully understood. In addition, cancers often develop resistance to the drugs. Something else not clear at the end of World War II was exactly how nitrogen mustards kill cancer and other cells. Many years after the original work, modern molecular biology explained that the nitrogen mustards work by acting as alkylating agents. This means that they insert alkyl groups into DNA molecules in ways that introduce breaks, or mismatch its base pairs, thus preventing it from replicating itself. Other chemotherapy agents work by interfering with other cellular processes—for example, by taking the place of a key amino acid needed for a tumor’s metabolism.
Sixty years after the first use of poison gas in chemotherapy, cancer remains a stubborn foe, and all too often a deadly one. Unlike such diseases as smallpox, in cannot be eliminated by any single method. But the rate of survival of cancer patients will continue to improve as researchers find new weapons to use against it. Nitrogen mustard was the first pharmacological weapon added to this arsenal, and while it has never been used to take lives in battle, it has helped to save and extend thousands of lives in hospitals, clinics, and medical offices around the world.