Jayant Radhakrishnan
Chicago, Illinois, United States

When Sahachirō Hata developed a cure for syphilis while working in Paul Ehrlich’s laboratory,¹ Ehrlich began to look for other chemicals that could destroy infectious agents without affecting normal host cells. In 1907, he coined the term chemotherapy² and declared that “the optimal agent would combine high parasitotropism with low organotropism.”³ Ehrlich later turned his attention to cancer, but it would take another three decades until the first chemotherapeutic cancer agents were available for general use.

Sulfur mustard, or 2,2′-dichlorodiethyl sulfide, later known as mustard gas, was apparently first synthesized in 1822 by César-Mansuète Despretz and again in 1854 by Alfred Riche. At the time, no one paid attention to it. On January 1, 1860, two scientists separately noted that it was a severe irritant for any organ or body part exposed to it.^4,5 These reports too went unnoticed until 1917, when the Germans decided to use chemical warfare in World War I. After trying chlorine and phosgene, they settled on mustard gas, which caused severe burns on the skin and respiratory system that sidelined exposed soldiers for the duration of the war, even if it did not kill them immediately. It was so effective that England and France also developed and accumulated it. After the war, there was worldwide consensus to ban its future use, but stockpiles were protected and research continued on uninformed and unsuspecting servicemen who were not compensated when they showed up with long-term health issues. The research was intended to find more destructive agents for future use, while also identifying antidotes, as it was clear that many countries were developing agents for chemical warfare.

Following the attack on Pearl Harbor, the United States Office of Scientific Research and Development (OSRD) was tasked with developing antidotes that could block the deleterious effects of such agents. The dean at Yale, Dr. Milton C. Winternitz, made a top-secret deal with the government to do so and gave the job to two young pharmacologists, Louis Sanford Goodman and Alfred Zack Gilman.⁶ They had access to studies based on German use of mustard gas in World War I. Two studies from 1919 by Edward and Helen Krumbhaar studied seventy-five patients who were exposed to mustard gas in France. An initial leukocytosis was followed by profound leukopenia about two weeks after exposure. If the leukocyte count fell below 5,000/mm³, recovery was rare, as their defenses were so diminished that they developed severe infections and died, even from organisms that were normally relatively benign. They found scant evidence of regenerating white blood cells in the bone marrow.^7,8 Another study was by Adair and Bagg, who treated superficial localized cancers in thirteen patients with mustard gas, which is a contact vesicant.⁹

Goodman and Gillman determined that the most sensitive measure of toxicity of mustard gas or its analogues, such as nitrogen mustards [Tris-(2-chloroethyl)amine or Methyl bis-(2-chloroethyl)amine], was the swiftness with which polymorphonuclear leukocytes and lymphocytes disappeared from circulation. They recognized that this sensitivity of lymphoid tissues to the drug could be used to treat lymphoid malignancies, so they recruited anatomist Thomas Dougherty to help them, as he had a rat with a transplanted lymphoma growing on it. After two injections of 0.1 mg of tris ß-chloroethylamine, the tumor disappeared completely, but later recurred. The next dose also worked but less so, and when the tumor grew for the third time, the drug did not work.

These findings encouraged them enough to present the information to a surgeon, Dr. Gustaf E. Lindskog, and they asked him to find a suitable patient to experiment on. Dr. Lindskog identified “JD,” who had developed submandibular pain and swelling in January 1941 following a tonsillectomy in August 1940. A biopsy revealed a lymphosarcoma. The patient had been treated with surgical excision and radiation therapy, but by August of 1942, he was no longer responding to radiation and had developed respiratory distress. On August 27, he received the first dose, and two days later, the second of ten daily doses of the drug, which resulted in complete resolution of the tumor by the end of September. The tumor recurred by the middle of October and was treated with a three-day course with a good, but short-lived response. As in the rat, the tumor no longer responded to a third course of medication starting on November 6, and the patient died on December 1, 1942. After treating six more patients at Yale, Goodman, who was a physician in addition to being a pharmacologist, collaborated with researchers in many other institutions to conduct clinical trials. Because of wartime secrecy, they only received permission to publicize their findings in 1946. By then 150 patients had been treated. To comply with the government’s directive of complete secrecy, patients’ records never referred to nitrogen mustard (a derivative of mustard gas), but rather to “substance X” or a “lymphocidal.”^6,10,11

Despite proclamations after World War I that chemical warfare must be banned, Allied troops and Italian civilians were still exposed to mustard gas during World War II. On December 2, 1943, the Germans bombed the Italian port of Bari, where the Allies were offloading troops and supplies. One of the ships they sank was the SS John Harvey, with its load of 2,000 M41-A1, 100-pound US-made mustard bombs. Fearing that the Germans would use that information as an excuse to escalate to chemical warfare, a complete news blackout was ordered, and neither the troops nor those treating them were aware that they had been exposed to mustard gas.

Military and civilian facilities became overloaded with those who were injured or burned directly by bombs. Many who had jumped overboard or had been thrown into mustard gas-containing waters appeared less injured, and so were covered in blankets and left alone in their soaked clothes. Hours later, they demonstrated local and systemic findings.^12,13

Eventually, the local authorities, suspecting that the Germans had dropped chemicals, called the Allied Force headquarters in Algiers for help. Lieutenant Colonel Stewart Francis Alexander, a cardiologist in peacetime but an expert in chemical warfare, was dispatched to Bari. He soon determined that mustard gas from an Allied ship was the cause of the problem and wrote a detailed report. Headquarters immediately classified the report and all evidence of it disappeared. Mention of mustard gas was deleted from all records and patient charts were altered, resulting in inadequate and improper treatment. This information remained classified until 1967. General Eisenhower eventually conceded that there was mustard gas on the ship but Prime Minister Churchill stuck to his denial to the very end. Ironically, the Germans were aware of the facts all along; the secrecy was for naught.

Immediately after the event, the Germans hired an Italian frogman in Bari to retrieve a shell casing as proof that the gas was of US origin. At the Nuremberg trials, Herman Goering said that they refrained from using mustard gas for practical and not humanitarian reasons. Their problem was that they were short of fuel following Allied bombing and were using horses to move troops, ammunition, and materials. They also knew that the Allies would retaliate with chemical weapons if they used mustard gas. They were concerned that might strand them completely as they had been unable to develop a gas mask that a horse could wear comfortably.¹³ Alexander continued his studies even after leaving Bari and rediscovered what the Krumbhaars had identified years earlier.^7,8 At the end of the war, Alexander chose to go back to his practice in New Jersey although his wartime boss, Colonel Rhoads, offered him a position in New York.

Alexander’s findings were hidden from the world but they were known to his superior, Colonel Cornelius Packard “Dusty” Rhoads, Chief of the Medical Division of the Chemical Warfare Service. While working for the Rockefeller Foundation in Puerto Rico in 1931, Rhoads had survived a major scandal when he bragged in a letter to his friend “Ferdie” (Boston researcher Fred Stewart) of having committed numerous racially-motivated murders and attempting others. He wrote that Puerto Ricans were “the dirtiest, laziest, most degenerate and thievish race of men ever to inhabit this sphere,” that they were “even worse than Italians,” and the island needed “a tidal wave or something to totally exterminate the population.” He added, “I have done my best to further the process by killing off eight and transplanting cancer into several more.” Rhoads was well connected and an important researcher. Consequently, two investigations absolved him and Ivy Lee, Rockefeller’s public relations expert, manipulated the news media, and advised Rhoads to claim the letter was a parody.

Rhoads’ career flourished without a hitch. He worked for the Rockefeller Institute until he became Director of the Memorial Hospital for the Treatment of Cancer and Allied Diseases in New York in 1939. He received the Legion of Merit for his wartime services and returned to Memorial Hospital after the war. He championed chemotherapy for cancer, having himself worked with mustard gas, and obtained funds from Alfred P. Sloan and Charles F. Kettering of General Motors to establish the Memorial Sloan-Kettering Cancer Center in 1945. Because of his abilities in fundraising and publicizing his work, he is often incorrectly believed to be the originator of cancer chemotherapy.^12,14 In reality, the age of local chemotherapy started in 1929 when Adair and Bagg employed it on their thirteen patients⁹ and that of systemic chemotherapy in 1942 when JD was treated,^10,11 not by Rhoads on August 6, 1945.¹² That day will be remembered instead for use of the ultimate destructive weapon on Hiroshima, Japan.

References

1. McIntosh J, Fildes P (1910). The theory and practice of the treatment of syphilis with Ehrlich’s new specific “606.” Lancet 176(4554):1684-1689 https://doi.org/10.1016/S0140-6736(00)62467-4.
2. Witkop B (1999). Paul Ehrlich and his magic bullets, revisited. Proc Amer Philosophical Soc 143(4):540-557 Stable URL: https://www.jstor.org/stable/3181987.
3. Valent P, Groner B, Schumaker U, Superti-Furga G, Busslinger M, Kralovics R, Zielinski C, Penninger JM, Kerjaschki D, Stingl G, Smolen JS, Valenta R, Lassmann H, Kover H, Jäger U, Kornek G, Müller M, Sörgel F (2016). Paul Ehrlich (1854-1915) and his contributions to the foundation and birth of translational medicine. J Innate Immun 8:111-120 doi: 10.1159/000443526.
4. Guthrie F (1860). XIII-On some derivatives from the olefines. QJ Chem Soc. 12(1):109-126. doi:10.1039/QJ8601200109.
5. Von Niemann A (1860). “Ueber die Einwirkung des braunen Chlorschwefels auf Elaylgas” [On the effect of brown sulfur chloride on ethylene]. Liebigs Annalen der Chemie und Pharmacie. 113(3): 288-292. doi:10.1002/jlac.18601130304.
6. Fenn JE, Udelsman R (2011). First use of intravenous chemotherapy cancer treatment: Rectifying the record. J Amer Coll Surg.212(3):413-417. doi: 10.1016/j.jamcollsurg.2010.10.018. Epub Jan 17, 2011.
7. Krumbhaar EB (1919). Role of the blood and bone marrow in certain forms of gas poisoning. I. Peripheral blood changes and their significance. JAMA 72(1):39-41. doi: 10.1001/jama.1919.26110010018009f.
8. Krumbhaar EB, Krumbhaar HD (1919). The blood and bone marrow in Yellow Cross gas (mustard gas) poisoning: changes produced in the bone marrow of fatal cases . .J Med Res. 40(3):497-508.3.
9. Adair FE, Bagg HJ (1931). Experimental and clinical studies on the treatment of cancer by dichlorethylsulphide (mustard gas). Ann Surg. 93(1):190-199. doi: 10.1097/00000658-193101000-00026.
10. Gilman A, Philips FS (1946). The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides. Science 103(2675):409-415 + 436 for references. doi: 10.1126/science.103.2675.409.
11. Gilman A (1963). The initial clinical trial of nitrogen mustard. Amer J Surg. 105(5):574-578. doi: 10.1016/0002-9610(63)90232-0.
12. Conant J (2020). The bombing and the breakthrough. How a chemical weapons disaster in World War II led to a US cover-up—and a new cancer treatment. Smithsonian Magazine September 2020. https://www.smithsonianmag.com/history/bombing-and-breakthrough-180975505/
13. O’Neill W (2021). The disaster at Bari: A secret revealed. Exploring History. Medium. Downloaded July 22, 2025. https://medium.com/exploring-history/the-disaster-at-bari-a-secret-revealed-ae4f74b189bd
14. Lederer SE (2002). “Porto Ricochet”: Joking about germs, cancer and race extermination in the 1930s. American Literary History, (online) 14(4):720-746. https://www.jstor.org/stable/3568022?
15. Starr D (2003). Revisiting a 1930s scandal, AACR to rename a prize. Science 300(5619):573-574. doi: 10.1126/science.300.5619.573.