The invention: The first successful chemotherapeutic for the treatment of syphilis
The people behind the invention:
Paul Ehrlich (1854-1915), a German research physician and chemist
Wilhelm von Waldeyer (1836-1921), a German anatomist Friedrich von Frerichs (1819-1885), a German physician and professor
Sahachiro Hata (1872-1938), a Japanese physician and
bacteriologist Fritz Schaudinn (1871-1906), a German zoologist
The Great Pox
The ravages of syphilis on humankind are seldom discussed openly. A disease that struck all varieties of people and was transmitted by direct and usually sexual contact, syphilis was both feared and reviled. Many segments of society across all national boundaries were secure in their belief that syphilis was divine punishment of the wicked for their evil ways.
It was not until 1903 that bacteriologists Elie Metchnikoff and Pierre-Paul-Emile Roux demonstrated the transmittal of syphilis to apes, ending the long-held belief that syphilis was exclusively a human disease. The disease destroyed families, careers, and lives, driving its infected victims mad, destroying the brain, or destroying the cardiovascular system. It was methodical and slow, but in every case, it killed with singular precision. There was no hope of a safe and effective cure prior to the discovery of Salvarsan.
Prior to 1910, conventional treatment consisted principally of mercury or, later, potassium iodide. Mercury, however, administered in large doses, led to severe ulcerations of the tongue, jaws, and palate. Swelling of the gums and loosening of the teeth resulted. Dribbling saliva and the attending fetid odor also occurred. These side effects of mercury treatment were so severe that many preferred to suffer the disease to the end rather than undergo the standard cure. About 1906, Metchnikoff and Roux demonstrated that mercurial ointments, applied very early, at the first appearance of the primary lesion, were effective.
Once the spirochete-type bacteria invaded the bloodstream and tissues, the infected person experienced symptoms of varying nature and degree—high fever, intense headaches, and excruciating pain. The patient’s skin often erupted in pustular lesions similar in appearance to smallpox. It was the distinguishing feature of these pustular lesions that gave syphilis its other name: the “Great Pox.” Death brought the only relief then available.
Poison Dyes
Paul Ehrlich became fascinated by the reactions of dyes with biological cells and tissues while a student at the University of Strasbourg under Wilhelm von Waldeyer. It was von Waldeyer who sparked Ehrlich’s interest in the chemical viewpoint of medicine. Thus, as a student, Ehrlich spent hours at this laboratory experimenting with different dyes on various tissues. In 1878, he published a topic that detailed the discriminate staining of cells and cellular components by various dyes.
Ehrlich joined Friedrich von Frerichs at the Charite Hospital in Berlin, where Frerichs allowed Ehrlich to do as much research as he wanted. Ehrlich began studying atoxyl in 1908, the year he won jointly with Metchnikoff the Nobel Prize in Physiology or Medicine for his work on immunity. Atoxyl was effective against trypano-some—a parasite responsible for a variety of infections, notably sleeping sickness—but also imposed serious side effects upon the patient, not the least of which was blindness. It was Ehrlich’s study of atoxyl, and several hundred derivatives sought as alternatives to atoxyl in trypanosome treatment, that led to the development of derivative 606 (Salvarsan). Although compound 606 was the first chemotherapeutic to be used effectively against syphilis, it was discontinued as an atoxyl alternative and shelved as useless for five years.
The discovery and development of compound 606 was enhanced by two critical events. First, the Germans Fritz Schaudinn and Erich
Hoffmann discovered that syphilis is a bacterially caused disease. The causative microorganism is a spirochete so frail and gossameric in substance that it is nearly impossible to detect by casual microscopic examination; Schaudinn chanced upon it one day in March, 1905. This discovery led, in turn, to German bacteriologist August von Wassermann’s development of the now famous test for syphilis: the Wassermann test. Second, a Japanese bacteriologist, Sa-hachiro Hata, came to Frankfurt in 1909 to study syphilis with Ehrlich. Hata had studied syphilis in rabbits in Japan. Hata’s assignment was to test every atoxyl derivative ever developed under Ehrlich for its efficacy in syphilis treatment. After hundreds of tests and clinical trials, Ehrlich and Hata announced Salvarsan as a “magic bullet” that could cure syphilis, at the April, 1910, Congress of Internal Medicine in Wiesbaden, Germany.
The announcement was electrifying. The remedy was immediately and widely sought, but it was not without its problems. A few deaths resulted from its use, and it was not safe for treatment of the gravely ill. Some of the difficulties inherent in Salvarsan were overcome by the development of neosalvarsan in 1912 and sodium salvarsan in 1913. Although Ehrlich achieved much, he fell short of his own assigned goal, a chemotherapeutic that would cure in one injection.
Impact
The significance of the development of Salvarsan as an anti-syphilitic chemotherapeutic agent cannot be overstated. Syphilis at that time was as frightening and horrifying as leprosy and was a virtual sentence of slow, torturous death. Salvarsan was such a significant development that Ehrlich was recommended for a 1912 and 1913 Nobel Prize for his work in chemotherapy.
It was several decades before any further significant advances in “wonder drugs” occurred, namely, the discovery of prontosil in 1932 and its first clinical use in 1935. On the heels of prontosil—a sulfa drug—came other sulfa drugs. The sulfa drugs would remain supreme in the fight against bacterial infection until the antibiotics, the first being penicillin, were discovered in 1928; however, they were not clinically recognized until World War II (1939-1945). With the discovery of streptomycin in 1943 and Aureomycin in 1944, the assault against bacteria was finally on a sound basis. Medicine possessed an arsenal with which to combat the pathogenic microbes that for centuries before had visited misery and death upon humankind.
See also Abortion pill; Antibacterial drugs; Birth control pill; Penicillin; Reserpine; Syphilis test; Tuberculosis vaccine; Typhus vaccine; Yellow fever vaccine.
