The Emperor of All Maladies. Siddhartha Mukherjee
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and muscled their way into textile factories all around Europe. By the mid-1880s, Germany had emerged as the champion of the chemical arms race (which presaged a much uglier military one) to become the “dye basket” of Europe.
Initially, the German textile chemists lived entirely in the shadow of the dye industry. But emboldened by their successes, the chemists began to synthesize not just dyes and solvents, but an entire universe of new molecules: phenols, alcohols, bromides, alkaloids, alizarins, and amides, chemicals never encountered in nature. By the late 1870s, synthetic chemists in Germany had created more molecules than they knew what to do with. “Practical chemistry” had become almost a caricature of itself: an industry seeking a practical purpose for the products that it had so frantically raced to invent.
Early interactions between synthetic chemistry and medicine had largely been disappointing. Gideon Harvey, a seventeenth-century physician, had once called chemists the “most impudent, ignorant, flatulent, fleshy,209 and vainly boasting sort of mankind.” The mutual scorn and animosity between the two disciplines had persisted. In 1849, August Hofmann, William Perkin’s teacher at the Royal College, gloomily acknowledged the chasm between medicine and chemistry: “None of these compounds have, as yet,210 found their way into any of the appliances of life. We have not been able to use them . . . for curing disease.”
But even Hofmann knew that the boundary between the synthetic world and the natural world was inevitably collapsing. In 1828, a Berlin scientist named Friedrich Wöhler211 had sparked a metaphysical storm in science by boiling ammonium cyanate, a plain, inorganic salt, and creating urea, a chemical typically produced by the kidneys. The Wöhler experiment—seemingly trivial—had enormous implications. Urea was a “natural” chemical, while its precursor was an inorganic salt. That a chemical produced by natural organisms could be derived so easily in a flask threatened to overturn the entire conception of living organisms: for centuries, the chemistry of living organisms was thought to be imbued with some mystical property, a vital essence that could not be duplicated in a laboratory—a theory called vitalism. Wöhler’s experiment demolished vitalism. Organic and inorganic chemicals, he proved, were interchangeable. Biology was chemistry: perhaps even a human body was no different from a bag of busily reacting chemicals—a beaker with arms, legs, eyes, brain, and soul.
With vitalism dead, the extension of this logic to medicine was inevitable. If the chemicals of life could be synthesized in a laboratory, could they work on living systems? If biology and chemistry were so interchangeable, could a molecule concocted in a flask affect the inner workings of a biological organism?
Wöhler was a physician himself, and with his students and collaborators he tried to backpedal from the chemical world into the medical one. But his synthetic molecules were still much too simple—mere stick figures of chemistry where vastly more complex molecules were needed to intervene on living cells.
But such multifaceted chemicals already existed: the laboratories of the dye factories of Frankfurt were full of them. To build his interdisciplinary bridge between biology and chemistry, Wöhler only needed to take a short day-trip from his laboratory in Göttingen to the labs of Frankfurt. But neither Wöhler nor his students could make that last connection. The vast panel of molecules sitting idly on the shelves of the German textile chemists, the precursors of a revolution in medicine, may as well have been a continent away.
It took a full fifty years after Wöhler’s urea experiment for the products of the dye industry to finally make physical contact with living cells. In 1878, in Leipzig, a twenty-four-year-old212 medical student, Paul Ehrlich, hunting for a thesis project, proposed using cloth dyes—aniline and its colored derivatives—to stain animal tissues. At best, Ehrlich hoped that the dyes might stain the tissues to make microscopy easier. But to his astonishment, the dyes were far from indiscriminate darkening agents. Aniline derivatives stained only parts of the cell, silhouetting certain structures and leaving others untouched. The dyes seemed able to discriminate among chemicals hidden inside cells—binding some and sparing others.
This molecular specificity, encapsulated so vividly in that reaction between a dye and a cell, began to haunt Ehrlich. In 1882, working with Robert Koch213, he discovered yet another novel chemical stain, this time for mycobacteria, the organisms that Koch had discovered as the cause of tuberculosis. A few years later, Ehrlich found that certain toxins, injected into animals, could generate “antitoxins,” which bound and inactivated poisons with extraordinary specificity (these antitoxins would later be identified as antibodies). He purified a potent serum against diphtheria toxin from the blood of horses, then moved to the Institute for Sera Research and Serum Testing in Steglitz to prepare this serum in gallon buckets, and then to Frankfurt to set up his own laboratory.
But the more widely Ehrlich explored the biological world, the more he spiraled back to his original idea. The biological universe was full of molecules picking out their partners like clever locks designed to fit a key: toxins clinging inseparably to antitoxins, dyes that highlighted only particular parts of cells, chemical stains that could nimbly pick out one class of germs from a mixture of microbes. If biology was an elaborate mix-and-match game of chemicals, Ehrlich reasoned, what if some chemical could discriminate bacterial cells from animal cells—and kill the former without touching the host?
Returning from a conference late one evening, in the cramped compartment of a night train from Berlin to Frankfurt, Ehrlich animatedly described his idea to two fellow scientists, “It has occurred to me214 that . . . it should be possible to find artificial substances which are really and specifically curative for certain diseases, not merely palliatives acting favorably on one or another symptom. . . . Such curative substances—a priori—must directly destroy the microbes responsible for the disease; not by ‘action from a distance,’ but only when the chemical compound is fixed by the parasites. The parasites can only be killed if the chemical compound has a particular relation, a specific affinity for them.”
By then, the other inhabitants of Ehrlich’s train compartment had dozed off to sleep. But this rant in a train compartment was one of medicine’s most important ideas in its distilled, primordial form. “Chemotherapy,” the use of specific chemicals to heal the diseased body, was conceptually born in the middle of the night.
Ehrlich began looking for his “curative substances” in a familiar place: the treasure trove of dye-industry chemicals that had proved so crucial to his earlier biological experiments. His laboratory was now physically situated215 near the booming dye factories of Frankfurt—the Frankfurter Anilinfarben-Fabrik and the Leopold Cassella Company—and he could easily procure dye chemicals and derivatives via a short walk across the valley. With thousands of compounds available to him, Ehrlich embarked on a series of experiments to test their biological effects in animals.
He began with a hunt for antimicrobial chemicals, in part because he already knew that chemical dyes could specifically bind microbial cells. He infected mice and rabbits with Trypanosoma brucei, the parasite responsible for the dreaded sleeping sickness, then injected the animals with chemical derivatives to determine if any of them could halt the infection. After several hundred chemicals, Ehrlich and his collaborators had their first antibiotic hit: a brilliant ruby-colored dye derivative that Ehrlich called Trypan Red. It was a name—a disease juxtaposed with a dye color—that captured nearly a century of medical history.
Galvanized by his discovery, Ehrlich unleashed volleys of chemical experiments. A universe of biological chemistry opened up before him: molecules with peculiar properties,