The significance to medicine wasn’t merely that a new tool for studying human and animal cells had been discovered. The tool could identify all kinds of cells, including bacteria. And, so the logic went, if a dye could recognize a specific class of bacterium, could it not also deliver a specific attack on the pathogenic ones? It was not a giant leap to imagine transforming a blob of paint that unerringly marked a dangerous trap into a compound—a magic bullet, perhaps—that would destroy it. Nor was it especially difficult to find the best place to start the search: wherever Robert Koch was working.* In 1891, Ehrlich joined Robert Koch at his Berlin Institute for Infectious Diseases.
The first step was understanding the magic bullets already present in humans and animals: the immune system. Even before Koch and Pasteur had demonstrated diseases were caused by microorganisms, the concept of immunity had been recognized and even classified. Victims of diseases like smallpox who survived were known to be immune to the disease thereafter. Thucydides, writing about the Plague of Athens, recognized that Athenians who had recovered from one encounter with the disease were protected against a second. The discovery of the germ theory suggested an explanation: Whatever provided immunity was attacking and destroying specific pathogens without harming the host. Could this germ-killing machinery be harnessed as a targeted therapy?
Though Ehrlich and his collaborators didn’t yet understand it in detail, the vertebrate immune system is composed of a dizzying array of components, some of them just long chains of amino acids, others complex cells, complete with specialized and deadly organelles. Some parts of the immune system are intelligence analysts, able to identify the nature of attacking pathogens; others are messengers, sending out chemical alarm bells to summon destroyer cells to the site of an invasion. There are even components, like the dendritic cells, that identify antigens, and train other cells, the T-lymphocyte white blood cells, to recognize them the next time they pay the host a visit.
The key categorical distinction used for the immune system is between those components that are innate—nonspecific defenses that respond to invaders that the organism has never encountered before—and those that are specific (or adaptive): the specialized defenses created by organisms only after they have encountered a specific pathogen. Innate first: When an organism—you, perhaps—encounters a microbe with evil intent, a dozen different proteins that are always circulating in the bloodstream send out a chemical alarm that activates another group of proteins known collectively as the cytokines. These molecules are folded in distinctive ways, permitting them to attach themselves to a pathogen, and hang on while sending off another alarm, summoning cell-based immune defenders like white blood cells. Meanwhile, other cell-based defenders, Ehrlich’s mastzelle, release chemicals like the histamines, which turn up the body’s thermostat, causing what is known as the inflammatory response: fever.
And that’s just the off-the-shelf, generic version of the innate system. Far more powerful are the bespoke defenses of an organism that has previously been exposed to a particular pathogen and has responded by tailoring a weapon specifically to destroy it. These specialized forces include cell-based troops like the B-lymphocytes manufactured in the bone marrow that create highly specific antibodies that hold on to the surface of invading cells; the T-lymphocytes that can destroy invaders by punching a hole in the invader’s membrane; and macrophages that can swallow and destroy them. The specialized immune system is a double-edged weapon; it depends on a very precise match between the supply of defenses and the demand for them. The inflammatory response can kill hosts as well as pathogens. Chronic lymphoid leukemia, one of the most dangerous—and common—cancers does its damage by overproducing B-cells that accumulate in the bone marrow, and so crowd out the ones needed to fight infections. Victims frequently die, not from cancer per se, but from the recurrent infections that their immune systems are no longer able to fight.
When Ehrlich and colleagues, most notably the physician Emil von Behring and the bacteriologist Hans Buchner, started studying the immune system in the 1890s, however, this taxonomy of immunity was still decades in the future. Their starting points were far simpler: Koch and Pasteur’s discovery that a specific microbe causes a specific disease, and that exposure to that microbe conferred immunity thereafter.
The first components of the immune system they discovered were the complex of antibacterial macromolecules found in blood serum, originally named “alexins” by Buchner, but renamed the “complement” by Ehrlich, to reflect his discovery that the thirty or so proteins that comprised it complemented the work of other proteins known as antibodies. If those molecules could be made to appear by exposure to the pathogens, then perhaps they could not only prevent future occurrences of a disease but, like Pasteur’s rabies vaccine, treat a new one—acting not as a vaccine, but as an antiserum. Behring started looking.
Born in 1854, Emil Behring (not yet “von”) was, like Ehrlich, a man who had come to adulthood after Bismarck’s 1871 consolidation of most of the Germanophone world as the Second Reich: Imperial Germany. Unlike the Jewish Ehrlich, he was training for a career in the Church before he transferred to a program in medicine, specifically military medicine. After garrison duty at a number of German army bases, he found his way—again like Ehrlich—to an orbit around one of the two great founders of the science of microbiology, at Koch’s Hygiene Institute in 1888, and, after 1890, the Institute for Infectious Diseases.
Also in 1890, Behring and his colleague, a visitor from Japan named Kitasato Shibasaburo, engineered the first real breakthrough in serum therapy. Ever since Jenner, the immune system had been activated by exposing its host to a pathogenic organism. Behring and Shibasaburo discovered that the immune system could be used to cure disease by exposing the host not to a pathogenic organism itself, but to the specific toxin released by most pathogens: the toxin that caused the symptoms of disease.
Their first practical demonstration of this discovery was used to treat a very dangerous disease, indeed: diphtheria. Corynebacterium diphtheriae was first identified by the Swiss pathologist Edwin Klebs in 1883 (the toxin produced by the bacteria was first identified in 1888 by Pasteur’s colleague Emile Roux and independently by the Swiss physician Alexandre Yersin, who would later give his name to the bacterium that causes bubonic plague: Yersinia pestis). Diphtheria was then afflicting more than fifty thousand Germans annually with sore throats, fever, and the disease’s characteristic membrane covering the tonsils and pharynx.* Up to five thousand would die. So when Behring and Shibasaburo announced, in 1891, that they were able to cure infected rats, guinea pigs, and rabbits by injecting them with a heat-weakened version of the toxin produced by C. diphtheria, it was very big news indeed.
The announcement was made well in advance of a proven therapy. Until 1897, when Ehrlich established a standardized unit for measuring diphtheria toxin, the antitoxin was at best unreliable, at worst dangerous. The immediate significance of the enthusiasm that greeted antiserum therapy wasn’t on diphtheria treatment, but on an even more consequential aspect of medical history: It attracted the interest of Germany’s industrial chemists. In 1892, Behring signed on to collaborate on the production of a diphtheria antitoxin with the Hoechst chemical company, based in Frankfurt-am-Main.
The company was then barely thirty years old, but had nonetheless seen its name change three times: from Teerfarben Meister, Lucius & Co. to Meister Lucius & Brüning to Farbwerke vorm. Meister Lucius & Brüning AG. By the time they went into business with Behring, the founders had evidently decided that simplicity was the better part of vanity and renamed their company Farbwerke Hoechst AG, since Hoechst (or Höchst) was where their first factory was located. The company’s primary business is revealed in its original name: The German Teer means “tar.” Farben translates as “color,” or more appropriately, “dye.”
That Behring would collaborate with a dye company wasn’t exactly unusual. To a very great degree, the chemical industry
in the late nineteenth century was the dye business: Dyes were by far the largest and most lucrative chemical process yet known, and enormously more profitable than, say, medicine. Vegetable-based dyes extracted from madder root, indigo plants, insects, and even shellfish, which was the source of the ancient dye known as “Tyrian purple,” have been used for at least three thousand years and probably longer to color textiles, but it took the scientific advances of the Industrial Revolution to create the first synthetic dyes. Most important of all were the aniline dyes, the organic compounds combined in a chemist’s lab.* Beginning in the 1830s, anilines had been extracted from coal tar; the same chemist who had distilled Joseph Lister’s carbolic acid from creosote also discovered that calcium hypochlorate could turn coal tar into a spectacular indigo dye. By the 1850s, the English chemist William Henry Perkin had accidentally discovered the first synthetic aniline dye, which he named mauveine. Even better, he had discovered a chemical breakthrough that revealed how to produce it by the carload, and the chemical industry was off to the races. Two other German chemists, Carl Liebermann and Carl Graebe, managed to isolate and synthesize alizarin, the active component in the madder root that had been used as a red dye since ancient Egypt. In 1870, Adolf von Baeyer did the same for indigo.
Since dye companies were always looking for innovative methods of producing color, a mastery of tissue staining was a prized talent. It’s therefore no coincidence that Hoechst brought Ehrlich—who had stained his first mast cells with aniline dyes—and Behring together. One of the many talents Ehrlich had cultivated was the ability to visualize the structure of dye molecules in three dimensions. By the end of the 1880s, Ehrlich, despite having no formal training as a chemist, had authored more than forty research papers on the chemistry of dyes and developed a dozen different staining methods using them. Working with Hoechst, and Behring, ought to have been a highly productive business; and it would have been, but for the very different objectives of a chemist working for an industrial lab rather than a hospital or university. Though Ehrlich had taken the precaution of taking out a basic patent on his method of standardizing diphtheria serum antitoxin, a fair reading of the subsequent events is that Behring managed to void those agreements in order to secure greater profits for himself from the collaboration with Hoechst.
The result was the poisonous transformation of the once close collegiality between two of Robert Koch’s greatest protégés into the same sort of lifelong hostility that characterized the relationship between Koch and Pasteur. It wasn’t merely the patent dispute. Ehrlich objected even more strongly to Behring’s attempt to profit from Koch’s tuberculin, producing a version marketed by Hoechst, even though the compound had already been shown to be useless. This was a point that Ehrlich made over and over again. “I must . . . be no longer exposed to Behring’s crass egotism and money-grubbing. I am not in the least inclined to . . . be subservient to his business shenanigans. I have no mind whatsoever to convert my Institute into a branch establishment or business venture of Behring’s. . . . [He] will now bad-mouth me everywhere, but my conscience is untroubled, and whatever he may be up to doesn’t faze me in the least.”
In any case, Ehrlich was searching for something bigger than antiserums. Though he joined Berlin’s Institute for Serum Research and Serum Testing (a grand name for a lab built in an abandoned bakery) in 1896 and continued his work on toxins when he moved to Frankfurt-am-Main’s Institut für Experimentalle Therapie in 1899, he already knew the limitations of antiserum therapy. Behring had shown that diseases could be caused not only by microbes, but also by toxins produced by the microbes, and that the body could produce a therapeutic response once exposed to the toxin. Turning this insight into a therapy, however, proved harder than expected. Antiserum therapy depends on the immune system’s ability to recognize a particular toxin: to identify it from its surface appearance. However, while some of the most dangerous toxins—exotoxins—are found on the surface of bacterial invaders, most bacterial diseases are caused by endotoxins, which do their damage only when the bacterial cell is ruptured. Since antiserum therapy only worked with exotoxins, it was effective against a limited number of pathogens. If the antiserum gun was firing magic bullets, very few of them were going to find their targets.
This didn’t mean that Ehrlich’s time in Berlin or Frankfurt was wasted; far from it. In 1897, he developed a truly revolutionary theory about the geometric relationship between an antigen and an antibody: the so-called side-chain theory.
Side-chain theory proposed that the membranes that enclosed the cells of multicellular animals were extremely complex chemical machines, each of whose components—Ehrlich’s side chains—has an affinity for a particular nutrient needed by the cell. Normally, each side chain is a kind of combination lock that opens when it encounters a needed protein. If any foreign substances—bacteria, viruses, or toxins—fit the same lock, metabolic activity is blocked. The cell responds by producing similar side chains as replacements, but overdoes it—in Ehrlich’s words, “nature is prodigal.” The extra side chains are then sloughed off into the cell’s surrounding fluid; and each of them, by definition, possesses precisely the shape to combine with the invading antigen. It is as if the cell had produced a finely machined gear that fits perfectly with its pathogenic match: antigens that latch onto the invaders and produce all the actions of the immune response—chemical signaling, inflammation, and everything else. The side-chain theory, and its explication of the immune response, was such an elegant and comprehensive discovery that it would win Ehrlich the 1908 Nobel Prize in Medicine.*
A commonplace observation about the Nobel Prizes says that no important work is ever done by winners after collecting the award. In this as elsewhere, Ehrlich was exceptional. Not only could the physician and scientist have been recognized by the Nobel committee for revolutionary medical discoveries made even before the creation of side-chain theory—histological staining; the investigations of the toxins ricin and abrin, which revealed the timing of the immune response—but, as time would reveal, his greatest achievement was still to come. That achievement, the birth of chemotherapy, was, nonetheless, very much of a piece with his very first publication nearly three decades before, on the staining of microscopic structures. Like his mastzelle, Ehrlich’s magic bullet appeared only in proximity to coal tar–based dyes.
The argument at the core of Ehrlich’s Nobel Lecture, entitled “Partial Cell Functions,” was that the future of microbiology depended less on observational biology, and more on fundamental chemistry.
Chemistry is one of the younger sciences. If you could pluck Isaac Newton out of the seventeenth century and drop him into a twenty-first-century high school, he could teach at least the first few chapters of a contemporary physics course; the laws of mechanics, for example, are still the ones Newton postulated. For that matter, a second-century mathematician could do the same for a full year of geometry or trigonometry. Even biologists still name species using the Linnaean classifications first published in 1735. In chemistry, though, hardly any idea that appeared before the French Revolution has survived except as an historical oddity, like the theory that chemical activity depended on a combustible substance called “phlogiston.”
The discipline began to come together with Antoine Lavoisier’s 1789 codification of the twenty-three known elements as substances that could not be broken into smaller components. In 1808, John Dalton in England and Joseph Gay-Lussac in France independently derived similar laws about the constituents of gases that led directly to the theory that all gases—all everything—were composed of impossibly small distinct elements known as atoms. The science had, for the first time, a usable conceptual framework.
Elements would be discovered over the course of the nineteenth century, including ones essential to life: sodium and potassium in 1807, calcium in 1808, iodine in 1811. Chemical analysis grew sharper and more precise with the introduction of dozens of apparatus. Since the time of Lavoisier, scientist
s have used combustion to examine the constituents of organic matter: burning the sample using a hollow glass blowpipe, trapping the carbon dioxide and water vapor produced, and measuring their volume in order to calculate how much hydrogen and carbon the sample originally contained. Gay-Lussac improved on this method by exposing samples to anhydrous calcium carbonate, which likewise trapped water vapor. In 1831, Justus von Liebig (the “Father of the Fertilizer Industry” for his discovery that nitrogen, in the form of ammonia, was the essential element in plant metabolism) invented the five-balled glass vessel he called the “Kaliapparat,” which trapped carbon dioxide as it passed through a filter of caustic potash, or potassium hydroxide.
Inevitably, as the tools of analysis improved, the temptation to create chemical compounds, which had been the dream of alchemists since antiquity, grew. The shift from analysis to synthesis—and, not so incidentally, from inorganic to organic chemistry—found its starting point with the German chemist Friedrich Wöhler’s 1828 synthesis of urea from simpler components such as cyanic acid and ammonia. In 1845, Hermann Kolbe synthesized acetic acid.
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