Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (6 page)

Another advance in reducing surgical infections was serendipitously introduced by William Stewart Halsted, professor of surgery at the Johns Hopkins University Hospital and Medical School in Baltimore. Halsted's OR nurse, Caroline Hampton, whom he would later marry, suffered dermatitis of her hands from repeated exposure to the sterilizing solution (mercuric chloride). In 1891 Halsted asked the Goodyear Company to make thin rubber gloves, which he then had her use to protect her hands.

Before long it became clear that the wearing of gloves—and later surgical gowns and masks, and the heat sterilization of instruments—by operating room staff prevented infection in surgical patients.

Pasteur himself took the next giant step as he turned his attention to a disease destructive to French poultry farms, chicken cholera. An unplanned discovery provided the first useful model for the preparation of a vaccine. Pasteur knew the value of cultivating a mind receptive to surprising occurrences. In his inaugural address at the age of thirty-two as professor and dean of the new Faculty of Sciences in Lille in 1854, he proclaimed a maxim that resonates to this day: “Where observation is concerned, chance favors only the prepared mind.” Repeatedly, his own activities proved to be striking illustrations of his statement.

If healthy chickens were injected with a culture of cholera microbes,
they invariably died within twenty-four hours. But one day in 1879, upon returning from a three-month-long summer vacation, he tried to restart his experiments, using a culture he had prepared before leaving. He was surprised to discover that nothing happened: the injected chickens remained quite healthy and lively. With the genius for exploiting what looked like an experiment gone wrong, he followed with the next logical step. Injections of fresh virulent cultures into the same hens now failed to produce the disease. Pasteur immediately recognized the significance of what he had blundered into. He had found a way of attenuating the cholera microorganisms artificially. He had succeeded in immunizing the chickens with the weak, old bacterial culture. A new truth was discovered: attenuated microbes make a good vaccine by imparting immunity without actually producing the disease. Vaccines could now be produced in the laboratory.

Two years later Pasteur produced a vaccine against anthrax, a highly contagious disease that was killing large numbers of cattle in Europe. It was also known as “wool sorters’ disease” because people contracted it from their sheep. In 1885 Pasteur had a triumphant success with the introduction of a vaccine against the terrifying disease rabies. Three years later the Pasteur Institute was established in Paris, becoming, in time, one of the most prestigious biological research institutions in the world.

2

The New Science of Bacteriology

The meteoric rise of Robert Koch (pronounced “coke”) from obscure country doctor to international celebrity was based on his talent for developing techniques for the isolation and identification of microbes. When he was a young physician in a small town near the German-Polish border, his wife bought him a microscope for his birthday, and he started looking at microbes as a pastime in a makeshift laboratory partitioned from his living room by a dropped sheet. By 1876, at the age of thirty-three, he had discovered the bacterium that causes anthrax. Within two years he published his monumental paper
Investigations Concerning the Etiology of Wound Infections,
scientifically proving the germ theory beyond doubt.
¹

Koch's landmark papers generated much excitement because he transformed the concept of what caused so many diseases. He would go on to establish with the clarity and purity of Euclidean logic the essential steps (“Koch's postulates”) required to prove that an organism is the cause of a disease: that the organism could be discoverable in every instance of the disease; that, extracted from the body, the germ could be produced in a pure culture, maintainable over several microbial generations; that the disease could be reproduced in experimental animals through a pure culture removed by numerous generations from the organisms initially isolated; and that the organism could be retrieved from the inoculated animal and cultured anew.

His painstaking work transformed bacteriology into a scientifically
based medical discipline. In 1891, three years after the Pasteur Institute was established in Paris, the German government founded the Koch Institute for Infectious Diseases in Berlin under his director-ship. In this era of European imperialist expansion into Africa, Asia, and the Indian subcontinent, he discovered the bacillus that causes cholera and studied the disease known as sleeping sickness in East Africa. Within a few years, through his pioneering methods, the bacterial causes of a host of other diseases—diphtheria, typhoid, pneumonia, gonorrhea, meningitis, undulant fever, leprosy, plague, tetanus, syphilis, whooping cough, and various streptococcal and staphylococcal infections—were uncovered, largely by his students.

An earlier chance observation by Koch had resulted in a critical breakthrough in culturing microorganisms. Up to this point, scientists had grown bacteria in flasks of nutrient broth. In the lab Koch just happened to notice that a slice of old potato left on a bench was covered in spots of different colors. He placed a spot from the potato slice on a slide and saw that all the microorganisms were identical and clearly different from those in another spot. He realized that each spot was a colony of a specific microorganism. The importance of this observation was that in broth all types of microbes are randomly mixed together and only with great difficulty can be selectively cultured. The potato allowed discrete colonies of separate bugs to grow, enabling distinction and selection from culturing for identification and testing. Serendipity pointed the way to obtain pure cultures.

The next step was to develop a more usable culture medium. Adding gelatin to the liquid broth resulted in a solid medium. A tiny loop of platinum wire was used to capture a droplet from a broth containing various species of bacteria, and it was streaked across the surface of the solid broth plate. But much to Koch's disappointment, the gelatin liquefied when placed in an incubator. His colleague, Richard Julius Petri, designed a shallow flat round dish with a cover, and agar, a jelling compound derived from Japanese seaweed, was used as the solid growth medium. Koch came upon this in an indirect way. Japanese seaweed was suggested by the wife of a colleague who had been posted in the Dutch East Indies; she had used it for making jam. In this way was born the Petri dish or “agar plate,” the mainstay of a
bacteriology laboratory. Clinical specimens such as throat swabs, sputum, or blood are streaked over the surface of the agar and then incubated at body temperature. Colonies containing millions of microbes shortly grow. The technique was revolutionary. Pure cultures of bacteria could now be obtained, enabling their isolation and identification.

Once he had a mechanism with which to isolate microorganisms, Koch was able to identify organisms that caused specific diseases. At this time he began focusing his attention on tuberculosis. Classically referred to as “consumption,” human tuberculosis was then responsible for one in seven of all European deaths. Identifying the organism was challenging work over a four-year period. The tiny rod-shaped organism was difficult to recognize with the staining techniques available at the time. Fortunately, a new advance came to Koch's attention. Paul Ehrlich, a young physician with a passion for chemistry, had developed a tissue stain called methylene blue. It was this stain that Koch used to detect the tiny rod-shaped bacillus in the tissues infected with tuberculosis. Because the bacillus grows slowly, it required the addition of blood serum to the agar as a nutrient and incubation for several weeks before colonies became apparent.
²

In 1882, in an evening address to the Berlin Physiological Society, Koch—now employed by the Imperial Health Office—thrilled the audience with the news that he had discovered the bacillus that causes tuberculosis,
Mycobacterium tuberculosis.
Koch's singular discovery led to his winning the Nobel Prize in 1905.

Inspired by Koch's success with the methylene blue stain, Ehrlich went on to devise and develop, over the years 1878–88, the technique of counterstaining, whereby the washing of a stained specimen with a second, acidic chemical removes the color from only specific cells or parts of cells and thus permits greater differentiation. He experimented unsuccessfully with a number of dyes to stain the TB bacillus until, after a few months, chance intervened. Finishing up his work late one night, Ehrlich found the small iron stove in his home laboratory a handy place to leave his stained preparations to dry overnight. The next morning, before the scientist was up, his housekeeper lit the stove without noticing the glass slides lying atop it. Upon entering the laboratory, Ehrlich was aghast at the sight of the fire in the stove. He rushed
to pick up his slides and inspect them through his microscope. What he saw was astonishing. The tubercle bacilli stood out wonderfully in bold color. The accidental heating had fixed the stain to the waxy-coated TB bacteria, allowing ready microscopic identification. This “acid-fast” staining technique is still used today.

3

Good Chemistry

By the middle of the nineteenth century, chemists had started synthesizing new substances with particular properties. The contributions of Friedrich Kekulé regarding the ring structure of the benzene molecule and Dmitri Mendeleev's periodic table in the 1860s provided a sound theoretical basis. An element's chemical properties were shown to be largely determined by two factors: the weight of its atoms, and the number of electrons each atom has in its outermost electron shell. With the understanding, toward the end of the nineteenth century, of the arrangement of electrons around a nucleus, atomic linkages could be constructed. Chemistry thus became a true science, capable of making predictions based on theory.

In this period, a new source of energy for illumination, coal gas, became widely employed. It was discovered that when coal is heated to high temperatures in the absence of air, it yields an inflammable gas. Coal gas became a popular replacement for candles and sperm-oil lamps. But perhaps more important, its ill-smelling waste product, coal tar, was quickly recognized as a gold mine. Coal tar contains aniline, an organic base, and azo compounds with nitrogen linkages attached to the benzene group. Benzene is a hydrocarbon compound, perhaps the most important of the organic compounds. It is the parent substance in the manufacture of thousands of other substances. Coal tar yields such varied products as dyes, drugs, perfumes, and plastics. In Germany synthetic dye production became a major
industry, with thousands of coal-tar dyes of varying colors and properties.
¹

Many commercial products were inventions rather than discoveries. By tweaking a chemical structure—adding a side chain here, modifying one there—the property of a compound could be programmed. In the German chemical industry, this activity led to what Georg Meyer-Thurow, a historian of science, calls the “industrialization of invention.”
²
Research was tightly managed within a bureaucratic structure. In an organization of industrial scientific laboratories, under a research administrator, invention was planned for and channeled through a series of steps based on past experience. But no one expected coal tar and its derived dyes to be the source of breakthrough drugs.

As a Jew, Paul Ehrlich was not eligible for appointments in academia or government research institutions in Germany. Koch, as director of the Institute for Infectious Diseases, reached out to him but, given the official constraints, could offer him only an unpaid position. Ehrlich gratefully accepted. Within a few years, he was working with Emil von Behring on a treatment for diphtheria. The name of this dreaded childhood disease is derived from the Greek for “leather,”
diphthera,
reflecting the leathery false membrane that coats the throat and palate, blocking the airways. The two men developed a diphtheria serum by repeatedly injecting the deadly toxin into a horse. The serum was used effectively during an epidemic in Germany. Ehrlich skillfully transformed diphtheria antitoxin into a clinically effective preparation, the first achievement that brought him world renown.

However, he was cheated out of both recognition and reward in a bitter experience with his colleague, von Behring. A chemical company preparing to undertake commercial production and marketing of the diphtheria serum offered a contract to both men, but von Behring found a devious way to claim all the considerable financial rewards for himself. To add insult to injury, only von Behring received the first Nobel Prize in Medicine, in 1901, for his contributions.

The experience with diphtheria stimulated Ehrlich to think about the way toxins and antitoxins work, and he visualized groups of atoms fitting together like a lock and key. He proposed that antigens—toxins
or other pathogens—lead to the generation of antibodies of reciprocal molecular shapes. This formulation is inherent in the term “antigen”—that is, leading to the
gen
eration of
anti
bodies. Although this hypothesis was proved false, Ehrlich's contribution was to conceptualize the process as essentially chemical responses and to establish the vocabulary of immunology. This would lead to a Nobel Prize in 1908 for Ehrlich and Ilya Metchnikoff of the Pasteur Institute in Paris, who shared the award for their work on immunity.

Ehrlich was a seminal thinker who had the unique ability to mentally visualize the three-dimensional chemical structure of substances: “Mine is a kind of visual 3-dimensional chemistry. Benzene rings and structural formulae disport themselves in space before my eyes. It is this faculty that has been of supreme value to me…. Sometimes I am able to foresee things recognized only much later by the disciples of systematic chemistry.”
³
His mind raced from natural antibodies to the range of dyes manufactured by the German chemical industry. These were very promising because, as histological staining made clear, their action was specific, staining some tissues and not others.