Salvarsan Provides a Cure for Syphilis and Ushers in the Field of Chemotherapy

Overview

The development of dyes that attach to specific biological tissues inspired a search for medicines that would attack disease-producing organisms while leaving healthy tissue intact. After testing over 600 arsenic compounds, German research physician Dr. Paul Ehrlich (1854-1915) announced the development of Salvarsan, a highly specific cure for syphilis, a chronic, debilitating venereal disease. While more modern antibiotic therapies have since replaced Salvarsan, Ehrlich's discovery has had a major impact on modern immunology, biochemistry, and chemotherapy.

Background

In 1900, syphilis was a much feared but little discussed disease. In over half of all cases, the disease, after first surfacing as a small, painless swelling, or sore, would enter a latent period, which could extend for many years and was void of any symptoms. The disease would then reappear as an infection of the nervous system, leading to debilitation, insanity, and death. It was not discussed in polite company because the disease was generally transmitted by sexual contact, although a pregnant woman with the disease could transmit it to her child, and during the disease's brief secondary phase it could be transmitted by more casual contact.

The nineteenth century had been a period of rapid advance in many areas of science and technology in Europe. In chemistry, the modern notion of atoms combining to form molecules took form, thanks to the work of the English chemist John Dalton (1766-1844), the Italian physicist Amadeo Avogadro (1776-1856), and many others. However, a full understanding that the atoms in a molecule had a definite arrangement in space did not develop until after 1874, when the tetrahedral arrangement of the chemical bonds around the carbon atom was proposed simultaneously by the Dutch physical chemist Jacobus van't Hoff (1852-1911) and the French chemist Joseph Le Bel (1847-1930).

In 1830, the English microscopist Joseph Jackson Lister (1786-1869) had devised a method of eliminating the distortions in earlier microscopes that had limited their usefulness. The discovery of the first aniline dye by British chemist William Henry Perkin (1838-1907) in 1856 led to the development of a vigorous dye industry, particularly in Germany. (Aniline is a colorless, poisonous liquid used to manufacture dyes, among other compounds.) With microscopes that could image microbes (microorganisms, especially those that cause disease) and dyes to stain them, a revolution in microbiology was at hand. Among the leaders in the new field was Robert Koch (1843-1910), a German physician who discovered the tuberculosis bacterium in 1882 and was named first director of the Berlin Institute of Infectious Diseases in 1891.

In the meantime, Paul Ehrlich had received his medical degree at the University of Leipzig in 1878, and as a student had developed an interest in the staining of microorganisms. Following a period of hospital practice and a convalescence of two years while he himself recovered from tuberculosis, he became Koch's assistant. There he worked on standardizing the therapeutic strength of the serums prepared by injecting disease organisms into animals. There, too, contemplating the highly specific affinity of dyes for specific tissues and the actions of serums on disease-producing organisms, he developed the beginnings of his "side chain theory." According to this theory, different types of cells were characterized by different chemical chains protruding into the surrounding medium. To stain them or to interfere with their action on a host organism, one had only to find a substance with molecules of a complementary shape that would bind chemically to the side chains; such a substance would act as a "magic bullet," affecting only the invading cell.

1899 Ehrlich became director of the Royal Prussian Institute for Experimental Therapy. To this was added, in 1906, the Georg Speyer House for chemotherapy, built and funded by a large private donation. Here, Ehrlich turned his attention to the diseases for which the immune response of animals was inadequate to produce an effective antiserum. Diseases caused by this group included sleeping sickness and yaws, diseases primarily of the tropics, and syphilis, which had afflicted Europeans at least since the end of the fifteenth century. Ehrlich hoped to cure these using not "serum therapy" but "chemotherapy"—the treatment of a disease with chemicals—using molecules specially built to attach to the pathogens. (A pathogen is any agent that causes disease.)

At the Institute, Ehrlich and his young Japanese associate, Kiyoshi Shiga (1870-1957), found an aniline dye, trypan red, that was particularly effective against trypanosomes, the parasitic protozoa that caused sleeping sickness and other diseases. In 1906, Koch introduced the use of atoxyl, an arsenic-containing compound that was thought to be related to the aniline dyes, against trypanosomes. Ehrlich was also interested in this drug, but determined that it attacked the optic nerve, and so could not be safely used on humans.

In 1905, the German microbiologist Fritz Richard Schaudinn (1871-1906) and a dermatologist, Erich Hoffman, discovered the organism, a spirochete—a spiral bacterium with some resemblance to the trypanosomes—that caused syphilis. Ehrlich began a systematic program to find an arsenic compound that would be effective, as well as safe to use, against syphilis. Over 600 compounds were synthesized and tested on rabbits infected with the spirochete, with careful attention to toxic side effects. After five years (during which time Ehrlich's work in immunology earned him a Nobel Prize in 1908), the researcher became convinced that the 606th preparation, which he named Salvarsan, was both safe and highly effective, as it attacked the disease germs but did not harm healthy cells. Thus, Salvarsan ushered in the new field of chemotherapy. He obtained a patent for the new compound and, with the assistance of a small number of physicians, began testing it on patients.

Ehrlich announced his discovery on April 19, 1910, at a Congress for Internal Medicine held at Weisbaden. The demand for Salvarsan grew rapidly; the Speyer House provided about 65,000 doses to physicians before the year had ended. A few individual patients reported adverse effects, and a few patients were not cured. After standardization of the injection procedure and the dosage, most of the problems did not recur. In time, the demand became too great for Ehrlich to handle, so he reached a manufacturing agreement with the Hochst Chemical Works, which began producing Salvarsan on a commercial basis in December, 1910. Salvarsan, as well as a more soluble and more easily administered form of the drug, NeoSalvarsan, would dominate the treatment of syphilis until the advent and widespread use of antibiotics in the 1940s.

Impact

Both the book of Genesis and the Greek myths include stories of man's fall from an idyllic, disease-free state as the result of disobedience of a divine command. While the development of the art of medicine reflects an acceptance of the idea that disease could have natural causes and could be treated by natural, rather than supernatural, means, the idea that one should not interfere with the course of a disease has never been completely abandoned. Karl Wassman, an individual who shared this view and the publisher of a sensationalist paper, launched an attack against Ehrlich, claiming that he had forced patients to undergo treatment against their will. The Frankfurt Hospital began legal proceedings against Wassmann. In court, Ehrlich appeared as a witness for the hospital. Wassman was found guilty of libel and his witnesses were discredited.

Penicillin, discovered by the Scottish bacteriologist Sir Alexander Fleming (1881-1955) in 1928, quickly replaced Salvarsan as the method of choice for treatment of syphilis. Despite the availability of treatment, syphilis remained a public health problem in the United States until the 1950s, when an aggressive public health campaign was launched to identify all victims of the disease and their sexual contacts. The notion that the victims of syphilis, at least racial minority victims, were less worthy of treatment than those suffering from other diseases might have played a role in the Tuskegee experiment, begun by the United States Public Health Service in 1932, and which continued through the 1960s. In this "experiment," the course of the disease was studied in a group of African American men, who were falsely led to believe that they were being treated. Over 100 men died while participating in this study.

Ehrlich's career includes a number of features that would come to play a prominent role in determining the course of medical research in the twentieth century. Many of his discoveries were dependent on new chemical ideas. He worked not in a university or hospital, but in an institute set up by the government to advance medical science. Although a doctor of medicine, he completed, in effect, a research apprenticeship under Robert Koch and then provided research training to a new generation of researchers. He was one of the first scientists to host researchers from other countries, notably Japan. When government funding proved insufficient, he was forced to turn to wealthy individuals for grants of funding to conduct research on a larger scale. He secured a patent for his new chemical compound and had to negotiate an agreement with a major commercial company in order to make his discovery available on a large scale. To prove the value and refine the technique of Salvarsan therapy, he conducted what today would be considered a large-scale clinical trial, with numerous physicians treating thousands of patients.

Ehrlich's side chain theory is still recognizable in several areas of biomedical science. Modern immunology has identified how the presence of characteristic groups, now called haptens, on invading cells induce the generation of antibody molecules that can recognize and bind to the invading cells. Somewhat similar ideas are found in enzymology in which enzymes molecules have active sites which provide a good geometric match to the substrates on which they act. The term chemotherapy is now most often used in connection with the treatment of cancer by chemicals. Substantial research resources are currently being devoted to finding new therapeutic agents, which like "magic bullets" will attack malignant cells, while leaving normal cells undisturbed.

Paul Ehrlich had an impact on popular culture, too. Like his fellow scientists Louis Pasteur (1822-1895) and Marie Curie (1867-1934) and inventors Thomas Edison (1847-1931) and Alexander Graham Bell (1847-1922), Ehrlich was memorialized by the movie industry: Dr. Ehrlich's Magic Bullet, starring Edward G. Robinson, was released in movie theaters in 1940.

DONALD R. FRANCESCHETTI