Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (7 page)

His earlier studies had indicated that different dyes react specifically with different cellular components. This led to the fundamental concept underlying his future work: the idea that chemical affinities govern all biological processes.
⁴

Shortly thereafter, his staining of the malarial parasite provided him with an opportunity. For centuries, malaria had been a disease encountered in Europe and rampant in Africa. It had long been believed to result from poisonous mists and evil vapors drifting off low-lying marshes. In time, with the suspicion that transmission of germs was due to mosquitoes, large parts of the Pontine swamps, breeding grounds for malaria, were drained. In the latter decades of the nineteenth century, the agent of the disease was identified, the parasite transmitted by female anopheles mosquitoes.

Bad Air

The term “malaria”—a misnomer derived from the Italian
mal aria
(“bad air”)—was first used in the 1740s by Horace Walpole (the same person who coined the term “serendipity” after reading the fable
The Three Princes of Serendip
). He described “a horrid thing called the mal'aria that comes to Rome every summer and kills one.”

Ehrlich began using methylene blue, the first aniline dye, to stain bacteria in 1880. By 1885, upon injecting it into a living frog, he found that it avidly stained nerve fibers. Even more startling was another experiment Ehrlich conducted with the dye, on a frog with a parasitic urinary infection. Studying the frog's excised bladder, he found that not only was the parasite still to be seen sucking blood from the frog tissue, but its nerve fibers were stained blue. Could the chemical dye, he reasoned, affect biological function to interfere with nervous transmission and exert an analgesic, or pain-killing, action in people?

Trials in humans with neuritic and arthritic conditions did not work. In 1891 he pursued to its logical conclusion the finding that malaria parasites stain well with methylene blue, and he administered the dye to a German sailor with a mild case of the disease. The patient recovered, but the dye was later proved to be of no value against the more severe manifestations of malaria experienced in the tropics. The dye also turned an individual blue. Nevertheless, this represented the first instance of a synthetic drug being successfully used against a specific disease.

Ehrlich had arrived at a totally new and revolutionary way to treat infections caused by microorganisms. He realized that such coal-tar-derived dyes bonded with substances like nucleic acids, sugars, and amino acids to form a definable chemical reaction. If, he reasoned, there were dye receptors—structures that received dyes—there might be drug receptors, substances fixed by microbes but not by the human host.

In this way, the concept of “magic bullets” was born. His basic idea, or hypothesis, was that since some dyes selectively stained bacteria and protozoa, substances might be found that would be selectively absorbed by the parasites and would kill them without damaging the host. Ehrlich termed fighting diseases with chemicals “chemotherapy” (a term that came to be used exclusively for cancer treatments) and later allowed that “initially, chemotherapy was chromotherapy,” meaning treatment with dyes.

Ehrlich combined some of the endearing characteristics of an absentminded professor with a mercurial mind. A small, wiry, unprepossessing man, he spent long hours absorbed in the laboratory, during which he typically smoked up to twenty-five strong cigars a day and frequently neglected to take his meals. Struck with an idea or an observation, he would scribble notes on his detachable shirt cuffs. To remind himself of an important forthcoming task or something he must not forget, he would on occasion send himself a postcard. He never claimed credit for the work of his assistants and always listed them as coauthors in the publications describing their joint work.

In 1899 Ehrlich was appointed director of the new government-supported Royal Prussian Institute for Experimental Medicine in the industrial city of Frankfurt. The government's desire to support research against infectious diseases overcame prevailing religious biases. Chemical companies, especially Hoechst and Bayer, were turning their attention to diseases as targets of industrial innovation, and hopes were high that Ehrlich could lead the industry into the burgeoning field of pharmaceuticals. A wealthy Jewish banker, and subsequently his widow, funded the building of Georg-Speyer-Haus, a laboratory with ample resources, to serve as the Research Institute for Chemo-therapy.

In 1906 Ehrlich turned his attention to the age-old, worldwide scourge of syphilis. By the turn of the twentieth century, this disease was of epidemic proportions throughout Europe, involving probably 15 percent of the adult population in major cities like Berlin, Vienna, Paris, and London. Generally referred to as “the pox,” syphilis was by this time known to be transmitted sexually.

A Shepherd Named Syphilus

The name “syphilis” comes from the poem
Syphilis, or the French Disease,
written in Latin by the sixteenth-century Italian philosopher and physician Girolamo Fracastoro, about a shepherd named Syphilus who offended the god Apollo and was punished with the world's first case of the disease. The poem was frequently translated and eventually was published in more than a hundred editions.

The general course of syphilis occurs in three stages. Within a few weeks of the initial exposure, the victim develops an ulcerous sore at the point of contact, which disappears after a few weeks. Fever, an extensive rash, and fatigue typically follow. These symptoms may recur over the course of a few years. A long, uneventful interval lasting for decades then ensues before the ravages of the systemic infection, known as tertiary syphilis, become apparent. It results in destructive lesions of the nervous system, heart, and bones. Both the long interval and the plethora of symptoms that are also common to other ailments often made diagnosis difficult. Treatment with oral mercury compounds was an ordeal and only marginally effective.

During the course of Ehrlich's research, two particular aspects demonstrated the remarkable vagaries of fortune. One had to do with a wrong hypothesis that nevertheless set him upon the right path, and the other was a laboratory misadventure that preserved the therapeutic miracle of the famous compound 606.

The causative bacterium of syphilis, a pale, threadlike, undulating spirochete later identified as
Treponema pallidum,
was discovered in 1905 by a German protozoologist and microbiologist, Fritz Schaudinn, with the dermatologist Erich Hoffmann. On the basis of what he took to be similarity of shape and movement, Schaudinn erroneously said that the spirochete was closely related to the trypanosomes. These comprise a group of protozoa, one form of which causes African sleeping sickness when transmitted to humans by tsetse flies.
Hoffmann personally emphasized the spirochete's similarity to trypanosomes when he visited Ehrlich's laboratory the following year. Trypanosomes have an elongated, somewhat spindly shape and a whip-like tail. This misidentification set Ehrlich upon the right path for an unsound reason. He was determined to find a chemical that would kill the spiral-shaped microorganism, and he had considerable experience with a form of arsenic in the treatment of trypanosome infections.

Ehrlich had read that an arsenical compound, optimistically named Atoxyl because it was thought to be free of toxic effects, had been successfully used in mice infected with trypanosomiasis at the Liverpool School of Tropical Medicine; however, it proved to cause optic nerve damage and blindness in up to 2 percent of humans. Ehrlich and his team worked unceasingly to prepare compound after compound that incorporated arsenic and, with methodical diligence, started testing them one by one. By 1907, compound no. 418 proved effective in humans but was unacceptable because a small number of patients exhibited severe and often fatal hypersensitivity. Chemical analogs continued to be produced in the search for a potential agent against trypanosomes.

That same year, the progenitor of compound no. 606 was prepared by one of Ehrlich's assistants. A piece of equipment, a vacuum apparatus necessary for reducing the compound, was lacking, so it stood on a shelf in the laboratory for more than a year before being reexamined. This proved to be a lucky lapse. If the apparatus had been available and the tests carried out, the compound might well have proved ineffective in the mice infected with trypanosomes and have been discarded, never to be tried against syphilis.

In the spring of 1909 Ehrlich was joined by Sahachiro Hata, a bacteriologist from Tokyo who had developed a method of infecting rabbits with syphilis. Under Ehrlich's direction, he undertook to retest, using the new animal model, every arsenical compound that the laboratory had synthesized over the preceding three years. The first 605 compounds they tried didn't have any effect. On August 31 of that year, they approached yet another cage with an infected rabbit exhibiting large syphilitic sores on its scrotum. Compound no. 606, which had been sitting on the shelf for almost two years, was injected
into the rabbit's ear vein. By the next day, its blood had been cleared of syphilis spirochetes and the sores were drying up and healing. With restrained glee, Ehrlich wrote, “It is evident from these experiments that, if a large enough dose is given, the spirochetes can be destroyed absolutely and immediately with a single injection!”
⁵

Ehrlich's secretary, Martha Marquardt, commented on the feverish activity behind this crowning achievement:

No outsider can ever realise the amount of work involved in these long hours of animal experiments, with treatments that had to be repeated and repeated for months on end. No one can grasp what meticulous care, what expenditure and amount of time were involved. To get some idea of it we must bear in mind that [the first hopeful compound] had the number 418, “Salvarsan” the number 606. This means that these two substances were the 418th and 606th of the preparations which Ehrlich worked out. People often, when writing or speaking about Ehrlich's work, refer to 606 as the 606th experiment that Ehrlich made. This is not correct, for 606 is the number of the substance with which, as with all the previous ones, very numerous animal experiments were made. The amount of detailed work which all this involved is beyond imagination.
⁶

The medical historian W. I. B. Beveridge wrote that Ehrlich's discovery of the cure for syphilis “is perhaps the best example in the history of the study of disease of faith in a hypothesis triumphing over seemingly insuperable difficulties”
⁷
—the hypothesis being the belief that a substance could be found that would be absorbed by the microbe and then be the source of its undoing.

Two young laboratory assistants at Ehrlich's institute injected themselves with the yellow crystalline powder dissolved in water to find out the right doses and test the toleration of 606. The preparation proved successful. Its chemical makeup directed the arsenic poison to the spirochete rather than to the patient. When 606 (generic name arsphenamine) was licensed to Farbwerke Hoechst near Frankfurt in a
contract with Georg-Speyer-Haus, it was marketed under the proprietary name Salvarsan—an arsenical salvation. Ehrlich chose not to make the contract with himself. He asked for only a modest interest in it, which was laid down in an agreement with the company.

The drug was eagerly sought by both physicians and patients, and large clinical trials in patients with syphilis were promptly undertaken. About 65,000 doses were provided free by Speyer-Haus from June to December 1910, until Hoechst Chemical Works could produce vast commercial quantities. The press throughout the world trumpeted the success of the treatments. A more easily used form, named Neosalvarsan, was soon brought to market. But even here, the intensity of the effort is evident in that Neosalvarsan was compound no. 914, more than three hundred compounds after 606.

Ehrlich found a great source of happiness in the first postcard he received from a cured patient. He kept this always in his wallet in the breast pocket of his coat.

Sometime after the outbreak of World War I in 1914, freed from patent protection, British and French scientists began collaborating to synthesize the drug, and 94,762 injections were administered by the French Military Medical Services alone. While some might find the title of Fracastoro's poem of 1530,
Syphilis sive morbus Gallicus
(
Syphilis, or the French Disease
) vindicated, this large figure provides an index of the widespread extent of venereal disease at the time. Neosalvarsan remained the only serious treatment for syphilis until the advent of penicillin in the 1940s.

Nazi Gratitude

When the Nazis came to power in 1933, they confiscated all books about Ehrlich and burned them in an attempt to expunge his name from German history. In 1938 his widow and family fled to the United States.

After Salvarsan was discovered, there was widespread hope that other chemical “salvations” would be rapidly uncovered. Optimism
ran high that an arsenal of “magic bullets” could be directed against man's ills. In 1913 Ehrlich enthused, “In the next five years we shall have advances of the highest importance to record in this field of research.” But this was not to be the case. Many compounds, including some new synthetic dyes, were tried by many researchers against the common bacterial diseases. Over and over, each failed. Dashed hopes and pessimism reigned over the next two decades.

Toward the end of his career, Ehrlich took stock of his experiences. He had earlier prophesied, “It will be a caprice of chance, or fortune, or of intuition which decides which investigator gets into his hands the substances which turn out to be the very best materials for fighting the disease, or the basal substances for the discovery of such.”
⁸
And, in fact, it was a “caprice of chance or fortune” that yielded the next triumph of the new art of chemotherapy, the sulfonamides—not five but twenty-five years later.