Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (9 page)

The Nazis versus the Nobelists

In October 1939 the forty-four-year-old Domagk was awarded the Nobel Prize in Physiology or Medicine.
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In announcing their selection one month after Germany's invasion of Poland, the Nobel Committee in Sweden displayed not only its integrity but also its bravery. The National Socialist government had been hostile to the Nobel Committee since 1936 when the Peace Prize was awarded to the German radical pacifist writer Carl von Ossietzky, who had been imprisoned in 1932 for exposing German rearmament. At the time, he suffered from pulmonary tuberculosis and, following the award, he was transferred—in a public relations gesture—to a hospital, where he soon died. After this incident, the Hitler regime established a Nazi Party Prize that could be won only by a German of impeccable Aryan ancestry and decreed that acceptance of a Nobel Prize was forbidden.

Domagk sought advice from the authorities on whether it would be possible to accept the prize. Two weeks later he was arrested by the Gestapo and forced to send a letter drafted for him by the Nazi government refusing the prize. After being released from jail, he confided in his diary: “My attitude to life and its ideals had been shattered.”
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When he was arrested a second time while traveling to Berlin for an international medical conference, he realized that he was under constant surveillance and thereafter acted cautiously to protect himself and his family. These experiences plunged him into years of depression. Only after the war, in 1947, was he able to travel to Stockholm to receive his Nobel Prize medal—but not the prize money, which had been redistributed. By this time, his breakthrough was eclipsed by a new class of drugs: antibiotics.

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Once sulfanilamide was in the public domain, pharmaceutical houses undertook a frenzied search for even more effective analogs. Foremost among these was the British firm of May and Baker, a subsidiary of the French chemical firm Rhône-Poulenc. Over the best part of three years, its chemists tweaked Prontosil's formula in a wide variety of ways and tested no fewer than 692 separate compounds. Their system of methodical trial-and-error yielded no good results until it was blessed by serendipity.

The true brew turned out to be a compound in a dusty bottle prepared seven years previously without any antimicrobial action in mind. It would shortly evolve into a form known as sulfapyridine. The historian of science John Lesch uncovered the event:

One day in October 1937, someone in the laboratory… noticed an old bottle sitting on the shelf. It turned out to be a sample of the base aminopyridine, prepared by a chemist named Eric Baines back in 1930 for another chemist who had since left the company. The sample… had stood on the shelf collecting dust ever since. Looking back two and a half decades later, company chemists… agreed that it would have been very unlikely that this compound would have been prepared for use in the sulfanilamide derivatives program. But since it was there, “at the front of the third shelf on the left hand side of the cupboard,” as another chemist, L.E. Hart, recalled, it was used. “Well, you know what would happen very much in those days,” Baines remarked to company colleagues in 1961, “you would set out to try and make something, and you would find something on the shelf, and you would try it.”
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Sulfapyridine not only proved more potent than sulfanilamide but also had a wider spectrum of antibacterial activity. It was effective against pneumococci, meningococci, gonococci, and other organisms.
It reduced the mortality rate among patients with the dreaded lobar pneumonia from 1 in 4 to only 1 in 25.

By the late 1930s and early 1940s the initiative for research pursuits passed to the British and the Americans.
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May and Baker began marketing sulfapyridine in 1938. It and the other new sulfa drugs were prescribed in huge quantities. By 1941 some 1,700 tons of them were given to 10 million Americans. Sulfadiazine, prepared by the American Cyanamid Company in 1940, was used extensively during World War II. The mortality rate among American soldiers in epidemics of meningitis was cut from 39 percent to 3.8 percent. (However, the course of gas gangrene, a bacterial infection following injury to muscles, characterized by bubbles of gas in the tissues, could not be successfully altered.) Every American soldier carried a packet of sulfa powder in his first-aid kit during World War II.

In late 1943 a singular incident involving Winston Churchill created a major impact on the popular imagination. The sixty-nine-year-old Churchill, in Tunisia for the planning of the invasion of Italy, developed life-threatening pneumonia. A course of sulfapyridine saved him, and, in typical Churchillian prose, he proclaimed that “the intruders were repulsed.”
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The “miracle drug” became a household term. The medical profession, impressed by reports of highly favorable clinical results, was now awakened to the new field of bacterial chemotherapy. A profusion of different “sulfa drugs,” all white crystalline powders, followed in quick succession.

The sulfa drugs were a breakthrough in the treatment of a host of deadly infections, such as pneumonia, meningitis, childbed fever, wound infections, erysipelas, mastoiditis, bacillary dysentery, gonorrhea, and most urinary infections.
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For the first time, the majority of these patients survived and recovered without lasting damage. These drugs would later be superseded by antibiotics, but the hope and faith in medical science engendered by Gerhard Domagk's discovery reverberate to this day.

The FDA Is Born

In 1937 shortly after young FDR Jr. recovered from his serious infection, a small Tennessee firm named Massengill and Company, which made pharmaceuticals for animals, began marketing a sulfa drug for people. To make it more easily administered to children in a sweet liquid form, they dissolved the drug in diethyl glycol, a commercial solvent used to make antifreeze, and sold it widely throughout the South as “Elixir of Sulfanilamide.” The company tested neither the solvent nor the final product for toxicity. Within weeks, more than a hundred people died, most of them children. The company's president refused to take responsibility and came to be convicted only on a technicality: the fact that the word
elixir
means a medicine containing alcohol, and there was none in the product sold.

Massengill's chief chemist committed suicide. The incident outraged the public, and Congress, and on June 15, 1938, President Franklin Delano Roosevelt signed into law the Food, Drug and Cosmetic Act, providing for safety tests on drugs before they could be marketed. This milestone legislation twenty years later spared the United States from the thalidomide tragedy.

5

Mold, Glorious Mold

In 1928 a quiet Scottish bacteriologist, Alexander Fleming, made a discovery that would change the course of history. But before Fleming came Sir Almroth Wright.

In charge of the bacteriology department at St. Mary's Hospital, a famous but run-down old hospital near the Paddington railway station far from the center of London, Wright was a brilliant larger-than-life physician and researcher who directed the hospital laboratory in the spirit of enlightened despotism. Contemporaries described him, with his large head, sandy hair, and moustache, as looking like the John Tenniel illustration of the Lion in Lewis Carroll's
Through the Looking Glass.
He was a strong-minded individual convinced of his own infallibility. His early scientific training was at several of the leading institutions on the Continent.
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Early in his career Wright became convinced that the only means of defeating a bacterial infection was through immunization, which was achieved in one of three ways: by having the disease, by getting vaccinated, or by using immune serum. The most remarkable advances at the turn of the century—Emil von Behring's diphtheria serum therapy, the first vaccines, and Ilya Metchnikoff's studies of phagocytosis (the immune response by white blood cells)—were in the realm of immunotherapy and exploited the natural defensive capabilities of the body to fight disease. Wright became single-minded in this pursuit.

Wright's earliest experiences were with the British military in India and then in South Africa, involving the prevention of typhoid fever
in the Boer War (1899–1902). Although the incidence of typhoid fever had fallen in cities with high standards of sanitation, Wright realized that these measures would not work with large armies in war, owing to the near impossibility of dealing effectively with waste. More than 60 percent of German deaths during the Franco-Prussian War were attributed to typhoid. Wright knew that typhoid fever was not just an infection of the bowel, but that death occurred when the bacilli invaded the bloodstream. He developed a culture of the typhoid germs killed by heat to serve as a vaccine.

During the Boer War, Wright was grudgingly given permission from the War Office to inoculate “such men as should voluntarily present themselves.” However, the army medical authorities were more worried by the body's reaction to vaccination—which often rendered a soldier unfit for several days—and therefore ordered many troopships departing for the war to throw caseloads of Wright's vaccines overboard. With only 4 percent volunteering to be vaccinated, 13,000 soldiers were lost to typhoid on the South African veld as against 8,000 battle deaths. (When giving evidence before a military tribunal, Wright was asked if he had anything more to say. His response was typically blunt: “No, sir. I have given you the facts. I can't give you the brains.”)
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Both Wright and the military were glad when the opportunity for him to go to St. Mary's Hospital arose in 1902. Here, with a group of dedicated young physicians, he undertook a long program of research on immunity and on techniques to stimulate immunity by vaccination in order to treat as well as prevent disease. A special component of this was the Inoculation Department, set up in 1907 for the production and sale of vaccines for a variety of illnesses ranging from acne to pneumonia. Independent of the hospital and medical school, it was, in effect, the first private clinical research institute in England.

An early recruit to this program was a recent prize-winning medical graduate of St. Mary's, Alexander Fleming. Fleming was born to a sheep-farming family in southwest Scotland in 1881. He excelled in school, and when he entered St. Mary's Hospital in London to study medicine, he fell under Wright's sway.

Fleming was just under five feet six inches in height, and slim. A
boyhood accident that had flattened the bridge of his nose may have given him the pugnacious appearance of a bantamweight boxer, but such an impression would have been very misleading. Invariably referred to as Flem, he was easygoing, good-tempered, and likeable, though very much the quiet type. (Fleming was generally so laconic that one of his colleagues claimed that trying to have a conversation with him was like playing tennis with a man who, when he received a serve, put the ball in his pocket.) He was respected for his common sense and ingenuity in experimental techniques.

Although Fleming's habitual silence contrasted sharply with Wright's flamboyance, the two men established a working relationship that would last until Wright's retirement at the age of eighty-five in 1946 (a year after Fleming won the Nobel Prize in Medicine). Through Wright's friendship with Paul Ehrlich, Fleming became one of the first to use Salvarsan to treat syphilis in Great Britain.

With the outbreak of World War I, both Wright and Fleming joined the Royal Army Medical Corps and were posted to Boulogne on the north coast of France. Here they studied the wounds and infection-causing bacteria of men who were brought straight from the battle-fields of Mons, Ypres, and the Marne. Many of these men died from septicemia or the dreaded gas gangrene. It became evident that gas gangrene and tetanus were due to wounds contaminated by organisms found in horse manure in the many farmers’ fields that war had turned into killing grounds.

Wright and Fleming made two significant observations regarding the ineffectiveness of the traditional use of antiseptic methods in curing established infections. Not only were antiseptics, such as carbolic acid, not reaching the many hidden crevasses of the deep, jagged war wounds typically caused by shrapnel, where bacteria could flourish, but the antiseptics themselves were destroying the white blood cells that were part of the body's natural immune system. Consequently, the infections spread rapidly. These findings reinforced Wright's contention that the enhancement of natural immunity with vaccines was superior to chemotherapy or antiseptic methods.

About half of the 10 million soldiers killed in World War I died not directly from explosives, bullets, shrapnel, or poison gases but
from infections in often relatively mild wounds. For his part, Fleming, then thirty-three, was forever affected by the suffering and dying he saw during the war, and he decided to focus his efforts on the search for safe antibacterial substances. From France in 1918 he wrote: “I was consumed by the desire to discover… something which would kill these microbes.” He would, he resolved, find “some chemical substance which can be injected without danger into the blood stream for the purpose of destroying the bacilli of infection.”
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Within three years, Fleming would surprise himself with a chance revelation. In November 1921 he had a cold. While he was working at his laboratory bench at St. Mary's, a drop from his runny nose fell on a Petri dish and “lysed” (dissolved) some colonies of bacteria. These common, harmless airborne microbes became translucent, glassy, and lifeless in appearance. Excited, Fleming prepared a cloudy solution of the bacteria and added some fresh nasal mucus to it. The young bacteriologist V. D. Allison, who was working with Fleming at the time, described what happened next: “To our surprise the opaque suspension became in the space of less than two minutes as clear as water…. It was an astonishing and thrilling moment.”
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