Ehrlich Introduces Salvarsan as a Cure for Syphilis

Date April, 1910

Paul Ehrlich’s development of Salvarsan, the first successful chemotherapeutic for the treatment of syphilis, ushered in a new age in medicine.

Locale Royal Prussian Institute for Experimental Therapy, Frankfurt, Germany

Key Figures

• Paul Ehrlich (1854-1915), German research physician and chemist
• Wilhelm Waldeyer (1836-1921), German anatomist
• Friedrich Theodor von Frerichs (1819-1885), German physician and professor
• Sahachiro Hata (1873-1938), Japanese physician and bacteriologist

Summary of Event

For centuries, syphilis was both feared and reviled. Transmitted by direct and usually sexual contact, the disease struck infamous and famous, lowborn and highborn alike with indifferent finality. Perhaps no other disease except leprosy evoked as much horror in the afflicted or as much revulsion in society. Across national boundaries, many people held the firm belief that syphilis was a divine punishment of the wicked. This view held in part because it was not until 1903 that Élie Metchnikoff and Pierre-Paul-Émile Roux demonstrated the transmittal of syphilis to apes, ending the long-held belief that syphilis is exclusively a human disease. In any case, the disease destroyed families, careers, and lives. It killed slowly, attacking the cardiovascular system and driving its infected victims mad by destroying the brain, but it was always fatal. There was no hope of a safe and effective cure prior to Salvarsan.

Before 1910, conventional treatment of syphilis consisted principally of the administration of mercury or, later, potassium iodide. In large doses, however, mercury caused severe ulcerations of the tongue, jaws, and palate, resulting in swelling of the gums, loosening of the teeth, drooling, and a fetid odor. These side effects were so severe that many preferred to suffer the disease to the end rather than undergo the mercury cure. About 1906, Metchnikoff and Roux demonstrated that if applied very early, at the first appearance of the primary lesion, mercurial ointments could be efficacious in the treatment of syphilis.

Once the disease had 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 lesions that gave syphilis its other name—the Great Pox. Death brought the only relief then available.

No one knew the cause of syphilis until 1905, when German researchers Fritz Schaudinn and Erich Hoffmann determined that a spirochete, Treponema pallidum, is the causative microorganism of the disease. This discovery made it possible for scientists to fight syphilis at last. The importance of Schaudinn and Hoffmann’s work is reflected in an inscription in dedication to Schaudinn by the German Medical Fraternity: “Dem Forscher, der den Keim entdeckte, der Liebeslust und Menschensaat verdarb und tief die Menschheit schreckte, zum Dank für seine grosse Tat” (To the scientist who discovered the germ that marred love and progeny and frightened mankind deeply, in grateful recognition of his greatest deed).

The “magic bullet” that was first found to cure syphilis is compound 606, later named Salvarsan. An arsenical arsphenamine, this compound was developed from another named atoxyl, which had been used in the treatment of trypanosomal infections such as sleeping sickness. The development of Salvarsan was the culmination of research that Paul Ehrlich began in 1874 while he was studying the chemical affinity of biological tissues for certain dyes such as aniline. It was also a departure from Ehrlich’s interest in tropical diseases, notably those of Africa, which were of concern because of the spread of imperialism by Western European governments, including Germany.

While a student at the University of Strasbourg under Wilhelm Waldeyer, Ehrlich became fascinated by the reactions of dyes with biological cells and tissues. Waldeyer sparked Ehrlich’s interest in the chemical viewpoint of medicine, and as a student Ehrlich spent hours at his laboratory experimenting with different dyes on various tissues. In 1878, he published Beiträge für Theorie und Praxis der histologischen Färbung (contributions to the theory and practice of histological staining), which detailed the discriminate staining of cells and cellular components by various dyes. This study led him to his discovery of mast cells.

Ehrlich joined Friedrich Theodor von Frerichs at the Charité Hospital in Berlin, where Frerichs gave Ehrlich complete autonomy in his research and freedom from clinical duties. During this time, Ehrlich described and named important white-cell family members—eosinophils, neutrophils, basophils, and acidophils. In 1886, Ehrlich developed methylene blue as an important selective stain for ganglia cells and nerve endings.

From 1889 to 1892, Ehrlich developed a diagnostic stain for the tubercle bacillus, the causative agent of tuberculosis, a microorganism discovered by Robert Koch in 1882. In 1904, Ehrlich developed trypan red, an effective antitrypanosomal agent of particular importance to equatorial African exploration and Western colonization. Ehrlich began studying atoxyl in 1908, the year he and Metchnikoff jointly won the Nobel Prize in Physiology or Medicine for their work in immunity.

Atoxyl was effective against trypanosome infection but also imposed serious side effects on the patient, not the least of which was a propensity to cause blindness because of its toxicity to the optic nerve. Ehrlich correctly determined the structure of atoxyl and further established that the pentavalent arsenic atom is therapeutically poor, whereas the trivalent arsenic atom is therapeutically superior in potency. 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 Salvarsan. Although it was the first chemotherapeutic found to be effective against syphilis, compound 606 was discounted as an atoxyl alternative and shelved as useless for five years.

The development of compound 606 was enhanced by two critical chains of events. First, Schaudinn and Hoffmann discovered that syphilis is a bacterially caused disease. The causative microorganism is a spirochete so delicate in substance that it is nearly impossible to detect through casual microscopic examination, but Schaudinn chanced on it one day in March, 1905, and this discovery led to August von Wassermann’s development of a test for syphilis—the now-famous Wassermann test. Second, Sahachiro Hata, a Japanese bacteriologist who had studied syphilis in rabbits, came to Frankfurt in 1909 to conduct research on syphilis with Ehrlich. 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 an antisyphilitic chemotherapeutic at the April, 1910, Congress of Internal Medicine in Wiesbaden, Germany.

The announcement of a cure for syphilis was electrifying, and immediately the demand for Salvarsan was overwhelming. The Höchst Chemical Company geared up for production of the drug after the Georg Speyer Haus, of which Ehrlich was director, produced about sixty-five thousand doses for distribution free of charge in 1911.

The use of the new compound was not without its problems, however. Medically, administration of Salvarsan was difficult, in part because its solubility was problematic. In addition, physicians sometimes did not comply strictly with the recommended administration regimens. A few deaths resulted from the use of Salvarsan, and it was not safe for treatment of the gravely ill. Some of these problems were overcome by further research, which resulted in Neo-Salvarsan in 1912 and Sodium Salvarsan in 1913. Although Ehrlich fell short of his own assigned goal of a chemotherapeutic that would cure syphilis with one injection, he was responsible for a very great achievement in the fight against this disease.

Significance

Given societal attitudes toward syphilis, some people saw the advent of Salvarsan as a challenge to divine justice against the wicked. Between 1910 and the outbreak of World War I in 1914, Ehrlich waged an endless battle against verbal and unfounded attacks on himself and Salvarsan. He handled the scientific and medical attacks with expert authority, but he was less able and less prepared to fend off the personal attacks launched against him. Two events vindicated Salvarsan and Ehrlich. In March, 1914, the Reichstag, the German legislature, investigated the charges leveled against Salvarsan by the medical community and found the compound as effective as Ehrlich maintained. Then, in May of the same year, in a libel suit brought by the Frankfurt Hospital, the principal detractor of Salvarsan was found guilty of libel and of bribing prostitutes to falsify statements concerning the hospital’s treatment of patients with Salvarsan.

The significance of the development of Salvarsan as an antisyphilitic chemotherapeutic agent cannot be overstated. The compound saved countless persons from horrible suffering and certain death. Because of his work on Salvarsan and on chemotherapy in general, Ehrlich was nominated for the Nobel Prize in Physiology or Medicine in 1912 and 1913. Ehrlich’s belief that specific chemical interactions take place between cells and certain substances was pivotal to the advancement of chemotherapy research.

With Ehrlich’s death in August, 1915, chemotherapy research came to a virtual standstill. The field appeared to have lost its direction, and it was several decades before any further significant advances in “wonder drugs” occurred. Then came the production of the first sulfa drug, Prontosil (sulfamidochrysoidine), in 1932 and its first clinical use in 1935. On the heels of this development came other sulfa drugs, which remained supreme in the fight against bacterial infection until they were displaced by antibiotics. The first antibiotic, penicillin, was discovered in 1928, but it was not clinically recognized until World War II. With the introduction of streptomycin in 1943 and Aureomycin, a tetracycline, in 1944, the assault against bacteria was finally on a sound basis. Medicine possessed an arsenal with which to combat the microbes that for centuries had visited misery and death on humankind.

Bibliography

Allen, Peter Lewis. The Wages of Sin: Sex and Disease, Past and Present. Chicago: University of Chicago Press, 2002. Discusses societal attitudes toward the victims of disease, especially sexually transmitted diseases, from the Middle Ages to the beginning of the twenty-first century. Chapter 3 looks specifically at responses to syphilis sufferers in early modern Europe. Includes bibliography and index.

Bender, George A. “Ehrlich: Chemotherapy Is Launched.” In Great Moments in Medicine: A History of Medicine in Pictures. Detroit: Northwood Institute Press, 1965. Succinctly describes Ehrlich’s studies leading to his work in chemotherapy in nontechnical, clear prose. Provides brief biographical data on Ehrlich and notes the contributions of other researchers who assisted or influenced Ehrlich.

Galdston, Iago. Behind the Sulfa Drugs: A Short History of Chemotherapy. New York: D. Appleton-Century, 1943. Chapters titled “Microbes and Dyes,” “Paul Ehrlich,” and “The Saga of Salvarsan” address Ehrlich’s work, including his interest in dyes and their reaction with cells, which formed the basis of his later work on immunity and chemotherapy. Provides a view of the field as it then existed.

Klainer, Albert S., and Irving Geis. Agents of Bacterial Disease. New York: Harper & Row, 1973. Discusses bacterial structure, morphology, and pathogenesis as well as various types of bacteria and their pathogenic properties and distinctions. The final chapter discusses chemotherapeutic agents. Intended for readers with some background in the biological sciences. Numerous illustrations.

Marquardt, Martha. Paul Ehrlich. London: William Heinemann Medical Books, 1949. Marquardt, Ehrlich’s secretary, provides a view of the man as both scientist and human being, including his interactions with other notable researchers of his day. Gives background on the historical scientific era in which Ehrlich’s work rested.

Reinfeld, Fred. Miracle Drugs and the New Age of Medicine. New York: Sterling, 1957. Excellent introduction to the subject presented in simple terms and with many illustrations. Discusses the history of drug treatment for disease and the development of drugs such as antibiotics.

Rodman, Morton J. Understanding Medications: The Hows and Whys of Drug Therapy. Oradell, N.J.: Medical Economics, 1981. Provides a discussion of the range of afflictions to which chemotherapy is applied. Describes drug interactions and contraindications. Aimed at readers with some background in biological and popular medical science.

Silverstein, Arthur M. Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession. New York: Academic Press, 2001. Focuses on Ehrlich’s many contributions to the field of immunology, placing them in the context of their times. Includes appendixes and indexes.

Taylor, F. Sherwood. “The Rise of Chemotherapy.” In The Conquest of Bacteria: From Salvarsan to Sulphapyridine. New York: Philosophical Library, 1942. Describes Ehrlich’s development of chemotherapy, beginning with his studies on trypanosomes. Also addresses Ehrlich’s interest in hookworm, malaria, amoebic dysentery, and leprosy.