Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (8 page)

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The Art of Dyeing

By the time World War I began, Germany's chemical industry had achieved world leadership. It had evolved in a series of steps begun in the 1880s that led from synthetic dyestuffs through pharmaceuticals to “chemotherapy.” The synthetic dye industry had originated with a stunning circumstance of serendipity in 1856 by an eighteen-year-old chemist, William Henry Perkin, trained at the Royal College of Chemistry in England.

Using a tiny laboratory that he had set up in his home, Perkin tried to synthesize the antimalarial drug quinine. The British Empire and other European nations were expanding their colonies into malaria-ridden areas of India, Southeast Asia, and Africa. Quinine, the only known cure and preventive for malaria, was commercially extracted from the bark of the South American cinchona tree. Quinine was in short supply, and its chemical structure unknown. In searching for a synthetic form, Perkin stumbled upon the first coal-tar dye, named mauve, or aniline purple.

The Origin of Ex-Lax

Spurred by Perkin's discovery, the Germans too began to synthesize dyes. One of these, with the tongue-twisting name phenolphthalein, became a worldwide medical remedy by sheer accident. At the turn of the twentieth century in Hungary, many vineyards
had been destroyed by a pestilence, and vintners turned to marketing artificial wine colored by natural dyes. Phenolphthalein, which had been used as an indicator of pH for more than thirty years, turns a purple-red color in an alkaline solution. When the Hungarian government began using phenolphthalein as an additive to identify adulterated white wines, an epidemic of diarrhea quickly broke out. This purgative action was a complete surprise,
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and the chemical's use in the wine industry was discontinued. Subsequently, a few commercial laxatives based on phenolphthalein (Ex-Lax, Feen-A-Mint) were distributed worldwide. Preparations were sold in gum and candy forms palatable to children, and the products became as well known as aspirin. In time, the active ingredient was replaced by another laxative, senna.

In 1918, after World War I, Germany was a depleted nation, virtually bankrupt, stripped of its colonies and thereby its textile empire. With neither the colonial sources of fibers nor the money to pay for imported wool and cotton, Germany feared that England would soon assume ascendancy in the world textile market. Germany harnessed its innovative minds and technological resources to emerge, within a decade, as the world's leading manufacturer of textiles, especially synthetic fibers. But textiles need to come in colors, and part of Germany's quest for market share in this burgeoning industry involved a search for a wide spectrum of dependable synthetic dyes.

Originally, independent firms with names like Farbenfabriken Bayer and Farbenwerke Hoechst developed the field of synthetic textile coloring.
Farben
is the German word for “colors.” In 1904 Hoechst merged with Farbwerke Cassella. Bayer joined forces with BASF and AGFA (AG für Anilinfabrikation) dye works, forming a group known as the little IG (
Interessengemeinschaft,
a coalition of shared interests). Bayer made a fortune in 1899 when it began marketing aspirin, the world's best-selling pain reliever, which it had made from the dyestuff intermediate salicylic acid. The gigantic conglomerate formed in 1925 that controlled all the German pharmaceutical houses, as well
as virtually all other branches of the German chemical industry, was named IG Farben. In this way, Germany's unrivaled eminence in the pharmaceutical, and particularly the “chemotherapeutic,” sector took root from developments in synthetic dyeing and staining. In 1924 the synthesis of a drug against malaria was announced, and within a few years success was achieved against several other tropical protozoal diseases, such as relapsing fever, sleeping sickness, yaws, leprosy, and filaria. But one fact engendered gloom: the utter failure of antibacterial chemotherapies over the two decades since Ehrlich's breakthrough.

With entrepreneurial vision, IG Farben now prepared to launch a systematic search, in combination with the development of new dye products, for antibacterial drugs along the lines laid down by Ehrlich. In 1927 it appointed a thirty-two-year-old physician and bacteriologist, Gerhard Domagk, to be director of its research laboratory at Elberfeld. Under his direction a laborious process of screening new compounds was undertaken, beginning with tests of effectiveness against various microbes in culture, followed by studies in animals, first to determine what doses could be tolerated and then their effects against infections; finally clinical tests in humans would be considered. He quickly concentrated on azo dyes, compounds in which two nitrogen atoms were linked by a double bond. First developed in 1909, these dyes were very resistant to fading from washing and light since they bond so effectively with the proteins in wool and silk. Might these agents react as well with the proteins of a bacterial cell?

Domagk was utterly single-minded in his approach. He soon focused his interest on a single bacterium, the streptococcus. Domagk was elegantly economical in his choice, aiming to treat a host of diseases due to one germ. Streptococcus was the cause of devastating infections that were both acutely life-threatening and chronically debilitating with frequent lethal effects. It was the cause of severe tonsillitis, infected glands in the neck, bacterial infections of the large joints (septic arthritis), puerperal fever, epidemics of scarlet fever, and rheumatic fever, which damaged heart valves and resulted in chronic kidney damage. Infection of the middle ear (otitis media) could result in
permanent deafness. Physicians also dreaded its skin manifestations when it spread into the tissues from an infected site: the scarlet wave of erysipelas (streptococcal cellulitis) and the sharp red lines indicating lymphatic spread. In such cases, amputation of an infected limb was often the only recourse. Most ominous was its tendency to cause blood poisoning, or streptococcal sepsis, which, along with its toxic products, could infect almost any site in the body. This invariably constituted a death warrant.

In 1932 Domagk was looking at a new brick-red azo dye that had a sulfonamide group attached to its molecule. It was being used to dye leather and was commercially marketed as Prontosil Rubrum. Tests in the laboratory showed it to be virtually inactive against bacteria in a Petri dish. Undaunted, Domagk went on to test it against streptococcal infections in laboratory mice.
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The results astonished him. Despite having been injected with a deadly species of streptococcus, every mouse inoculated with this new crystalline chemical was alive and frisky, running about in its cage. All those in the control group given that same bacterium but no red dye were dead.

Domagk was an intense researcher who was driven by an independence of thought. His close-shaven head and pale blue eyes gave him the appearance of an unemotional man. But witnessing those results in the laboratory cages, five days before Christmas, moved him to exaltation: “We stood there astounded at a whole new field of vision, as if we had suffered an electric shock.”
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IG Farben wasted no time in claiming its priority. On Christmas Day, it submitted an application for a German patent on Prontosil.

Over the next two years, as Domagk quietly investigated the new compound with the help of selected local physicians treating patients with streptococcal infections, several dramatic cures in humans testified to the new drug's effectiveness. The first patient was a ten-month-old infant severely ill with staphylococcal septicemia (blood poisoning), a condition from which no one had ever been known to recover. Treating the baby with Prontosil was a daring gamble on Domagk's part. If the child had not survived, it would not have been clear whether the drug or the disease had killed him. The child's skin turned red, and his
physicians were able to calm his excited nurse only by explaining that the drug was basically a dye. Within days, the child miraculously recovered. Prontosil was distributed for clinical trial in 1933.

In a dramatic twist of fate, a few months later Domagk was forced to use Prontosil to cure his own six-year-old daughter, Hildegard, who was facing a similar life-threatening infection. She had pricked her hand with an embroidery needle in the web of tissue between her thumb and index finger. The wound became infected with streptococcus, and the infection spread to the arm and then into the bloodstream. Swollen lymph nodes in the armpit were lanced of pus fourteen times, but the infection was relentless, and the surgeon recommended amputation of the child's arm. Domagk refused. In desperation, he took one of his precious experimental drug samples and treated Hildegard with it. Within two days her fever broke, and after repeated courses of the drug, she went on to recover fully—with, however, one unfortunate and permanent side effect: her skin turned a light reddish, lobsterlike color. This was not true of all patients who used Prontosil.

Early reports that “something was brewing in the Rhineland” regarding chemotherapy cures of streptococcal infections reached Britain by the summer of 1935. The brew was Prontosil. Used in an outbreak of puerperal sepsis (childbed fever) in 1936 in Queen Charlotte Maternity Hospital in London, the new “miracle drug” slashed mortality from 25 to 4.7 percent.

In February 1935 Domagk finally published his classic paper, which was modestly titled “A contribution to the chemotherapy of bacterial infections.”
competitors. IG Farben would have recognized that the active principle, sulfanilamide, was not patentable.

No One Ever Thought of Testing It

Sulfanilamide itself had been synthesized and described long before, in Vienna in 1908 by Paul Gelmo in the course of working on his doctoral thesis. Like many other synthetic chemicals of no use, it had been gathering dust on some laboratory shelves. It had been produced in huge quantities as a by-product in the dye industry, and nobody had ever thought of testing it as an antibiotic. Had its properties been known, sulfanilamide might have saved 750,000 lives in World War I alone. After the war, Gelmo was found eking out a precarious existence as an analytical chemist for a firm of printing ink manufacturers.

Domagk and his team of chemists may have been in a frantic race for a patentable analog. This concern for secrecy would explain why the IG Farbenindustrie did not respond to researchers at the Pasteur Institute in Paris who requested samples of Prontosil to investigate its inactivity in the laboratory. The Germans, of course, were pursuing an exclusive commercial product with huge potential profits. Not only scientific but also nationalistic rivalry was undoubtedly at stake.

In a breathtaking series of events, the French scientists Jacques Tréfouël and his wife Therèse, together with Frédéric Nitti and Daniel Bovet, quickly succeeded in synthesizing similar compounds on their own. Within nine months of Domagk's publication, their experiments not only verified his results but, in a compelling instance of fortune, uncovered what would prove to be the essential “wonder drug.”

They intended to test the curative powers of their chemical dyes on eight groups of mice injected with a highly virulent culture of streptococcus. Only seven dyes were readily available. For the eighth group, they reached for a long-neglected dust-laden bottle on their laboratory shelf containing a colorless mixture. This would turn out to be sulfanilamide, the chemical common to all the compounds in the
experiment. The next morning, the control group of mice—those not treated with a synthesized dye—were all dead. Those treated with Prontosil and analogs had been protected—as had, most surprisingly, the eighth group of mice treated with the colorless chemical. A “Eureka!” moment had been occasioned by chance.

Why Prontosil was inactive in vitro (in the test tube) but effective in vivo (in the body) became apparent and was soon proved. In the body, Prontosil is broken down to liberate the active principle, sulfanilamide, which alone is the agent against streptococcal growth. Furthermore, Tréfouël and his team demonstrated that sulfanilamide in contrast to Prontosil is active not only in vivo but also in vitro. They were amazed to find that its action was in no way related to its being a dye but rather was due to its containing sulfanilamide, which is not a dye. “From that moment on,” writes Bovet, “the patent of the German chemists would carry no more weight.”
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French patent law recognized Prontosil as a dye and not a medicine.

As reported in a French journal, the team's findings were presented as though they had been reached via deductive reasoning.
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But recalling the experiences fifty-one years later in a book, Bovet clearly describes them as a fortunate happenstance.
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IG Farben's euphoric hopes for huge profits from the marketing of Prontosil had been shattered.
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Sulfanilamide's derivatives were patentable, but all these products were cheap and easy to make. They had the further advantage, over Prontosil, of not turning the patient as red as a boiled lobster. These circumstances greatly helped the new antibacterial therapy to receive widespread acceptance.

Within two years of the publication of Domagk's paper, his cure made a splash on the other side of the Atlantic. In December 1936 twenty-two-year-old Franklin D. Roosevelt Jr., son of the president of the United States, developed a severe streptococcal tonsillitis that soon involved his sinuses. Blood-borne spread appeared imminent, and the prognosis was feared grave. But he was given sulfanilamide and made a rapid recovery. Newspaper accounts spread the miraculous potential of this new wonder drug. In America, such reports stimulated rapid growth of the pharmaceutical industry.

A new era dawned. An individual with a severe infection need not start making funeral arrangements. For the first time in history, patients suffering from overwhelming infections could be cured without surgery, simply by taking a course of tablets or injections.