Читать книгу The Emperor of All Maladies - Siddhartha Mukherjee, Siddhartha Mukherjee - Страница 19

Dyeing and Dying

Those who have not been trained in chemistry²⁰¹ or medicine may not realize how difficult the problem of cancer treatment really is. It is almost—not quite, but almost—as hard as finding some agent that will dissolve away the left ear, say, and leave the right ear unharmed. So slight is the difference between the cancer cell and its normal ancestor.

—William Woglom

Life is . . . a chemical incident²⁰².

—Paul Ehrlich

—as a schoolboy, 1870

A systemic disease demands a systemic cure—but what kind of systemic therapy could possibly cure cancer? Could a drug, like a microscopic surgeon, perform an ultimate pharmacological mastectomy—sparing normal tissue while excising cancer cells? Willy Meyer wasn’t alone in fantasizing about such a magical therapy—generations of doctors before him had also fantasized about such a medicine. But how might a drug coursing through the whole body specifically attack a diseased organ?

Specificity refers to the ability of any medicine to discriminate between its intended target and its host. Killing a cancer cell in a test tube is not a particularly difficult task: the chemical world is packed with malevolent poisons that, even in infinitesimal quantities, can dispatch a cancer cell within minutes. The trouble lies in finding a selective poison—a drug that will kill cancer without annihilating the patient. Systemic therapy without specificity is an indiscriminate bomb. For an anticancer poison to become a useful drug, Meyer knew, it needed to be a fantastically nimble knife: sharp enough to kill cancer yet selective enough to spare the patient.

The hunt for such specific, systemic poisons for cancer was precipitated by the search for a very different sort of chemical. The story begins with colonialism and its chief loot: cotton. In the mid-1850s, as ships from India and Egypt laden with bales of cotton unloaded their goods in English ports, cloth milling boomed into a spectacularly successful business in England, an industry large enough to sustain an entire gamut of subsidiary industries. A vast network of mills sprouted up in the industrial basin of the Midlands, stretching through Glasgow, Lancashire, and Manchester. Textile exports dominated the British economy. Between 1851 and 1857²⁰³, the export of printed goods from England more than quadrupled—from 6 million to 27 million pieces per year. In 1784, cotton products had represented a mere 6 percent of total British exports. By the 1850s, that proportion had peaked²⁰⁴ at 50 percent.

The cloth-milling boom set off a boom in cloth dyeing, but the two industries—cloth and color—were oddly out of technological step. Dyeing, unlike milling, was still a preindustrial occupation. Cloth dyes had to be extracted²⁰⁵ from perishable vegetable sources—rusty carmines from Turkish madder root, or deep blues from the indigo plant—using antiquated processes that required patience, expertise, and constant supervision. Printing on textiles with colored dyes (to produce the ever-popular calico prints²⁰⁶, for instance) was even more challenging—requiring thickeners, mordants, and solvents in multiple steps—and often took the dyers weeks to complete. The textile industry thus needed professional chemists to dissolve its bleaches and cleansers, to supervise the extraction of dyes, and to find ways to fasten the dyes on cloth. A new discipline called practical chemistry, focused on synthesizing products for textile dyeing, was soon flourishing in polytechnics and institutes all over London.

In 1856, William Perkin, an eighteen-year-old student at one of these institutes, stumbled on what would soon become a Holy Grail of this industry: an inexpensive chemical dye that could be made entirely from scratch. In a makeshift one-room laboratory in his apartment in the East End of London (“half of a small but long-shaped room²⁰⁷ with a few shelves for bottles and a table”) Perkin was boiling nitric acid and benzene in smuggled glass flasks and precipitated an unexpected reaction. A chemical had formed inside the tubes with the color of pale, crushed violets. In an era obsessed with dye-making, any colored chemical was considered a potential dye—and a quick dip of a piece of cotton into the flask revealed the new chemical could color cotton. Moreover, this new chemical did not bleach or bleed. Perkin called it aniline mauve.

Perkin’s discovery was a godsend for the textile industry. Aniline mauve was cheap and imperishable—vastly easier to produce and store than vegetable dyes. As Perkin soon discovered, its parent compound could act as a molecular building block for other dyes, a chemical skeleton on which a variety of side chains could be hung to produce a vast spectrum of vivid colors. By the mid-1860s, a glut of new synthetic dyes, in shades of lilac, blue, magenta, aquamarine, red, and purple flooded the cloth factories of Europe. In 1857, Perkin, barely nineteen years old, was inducted into the Chemical Society of London as a full fellow, one of the youngest in its history to be thus honored.

Aniline mauve was discovered in England, but dye making reached its chemical zenith in Germany. In the late 1850s, Germany, a rapidly industrializing nation, had been itching to compete in the cloth markets of Europe and America. But unlike England, Germany had scarcely any access to natural dyes: by the time it had entered the scramble to capture colonies, the world had already been sliced up into so many parts, with little left to divide. German cloth millers thus threw themselves into the development of artificial dyes, hoping to rejoin an industry that they had once almost given up as a lost cause.

Dye making in England had rapidly become an intricate chemical business. In Germany—goaded by the textile industry, cosseted by national subsidies, and driven by expansive economic growth—synthetic chemistry underwent an even more colossal boom. In 1883, the German output of alizarin²⁰⁸, the brilliant red chemical that imitated natural carmine, reached twelve thousand tons, dwarfing the amount being produced by Perkin’s factory in London. German chemists rushed to produce brighter, stronger, cheaper chemicals 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, a cosmos governed by idiosyncratic rules. Some compounds switched from precursors into active drugs in the bloodstream; others transformed backward from active drugs to inactive molecules. Some were excreted in the urine; others condensed in the bile or fell apart immediately in the blood. One molecule might survive for days in an animal, but its chemical cousin—a variant by just a few critical atoms—might vanish from the body in minutes.

On April 19, 1910, at the densely packed²¹⁶ Congress for Internal Medicine in Wiesbaden, Ehrlich announced that he had discovered yet another molecule with “specific affinity”—this one a blockbuster. The new drug, cryptically called compound 606, was active against a notorious microbe, Treponema pallidum, which caused syphilis. In Ehrlich’s era, syphilis—the “secret malady”²¹⁷ of eighteenth-century Europe—was a sensational illness, a tabloid pestilence. Ehrlich²¹⁸ knew that an antisyphilitic drug would be an instant sensation and he was prepared. Compound 606 had secretly been tested in patients in the hospital wards of St. Petersburg, then retested in patients with neurosyphilis at the Magdeburg Hospital—each time with remarkable success. A gigantic factory, funded by Hoechst Chemical Works, was already being built to manufacture it for commercial use.

Ehrlich’s successes with Trypan Red and compound 606 (which he named Salvarsan, from the word salvation) proved that diseases were just pathological locks waiting to be picked by the right molecules. The line of potentially curable illnesses now stretched endlessly before him. Ehrlich called his drugs “magic bullets”—bullets for their capacity to kill and magic for their specificity. It was a phrase with an ancient, alchemic ring that would sound insistently through the future of oncology.

Ehrlich’s magic bullets had one last target to fell: cancer. Syphilis and trypanosomiasis are microbial diseases. Ehrlich was slowly inching toward his ultimate goal: the malignant human cell. Between 1904 and 1908, he rigged several elaborate schemes to find an anticancer drug using his vast arsenal of chemicals. He tried amides, anilines, sulfa derivatives, arsenics, bromides, and alcohols to kill cancer cells. None of them worked. What was poison to cancer cells, he found, was inevitably poison to normal cells as well. Discouraged, he tried even more fantastical strategies. He thought of starving sarcoma cells of metabolites, or tricking them into death by using decoy molecules (a strategy that would presage Subbarao’s antifolate derivatives by nearly fifty years). But the search for the ultimate, discriminating anticancer drug proved fruitless. His pharmacological bullets, far from magical, were either too indiscriminate or too weak.

In 1908, soon after Ehrlich won the Nobel Prize for his discovery of the principle of specific affinity, Kaiser Wilhelm of Germany invited him to a private audience in his palace. The Kaiser was seeking counsel: a noted hypochondriac afflicted by various real and imagined ailments, he wanted to know whether Ehrlich had an anticancer drug within reach.

Ehrlich hedged. The cancer cell, he explained, was a fundamentally different target from a bacterial cell. Specific affinity relied, paradoxically, not on “affinity,” but on its opposite—on difference. Ehrlich’s chemicals had successfully targeted bacteria because bacterial enzymes were so radically dissimilar to human enzymes. With cancer, it was the similarity of the cancer cell to the normal human cell that made it nearly impossible to target.

Ehrlich went on in this vein, almost musing to himself. He was circling around something profound, an idea in its infancy: to target the abnormal cell, one would need to decipher the biology of the normal cell. He had returned, decades after his first encounter with aniline, to specificity again, to the bar codes of biology hidden inside every living cell.

Ehrlich’s thinking was lost on the Kaiser. Having little interest in this cheerless disquisition with no obvious end, he cut the audience short.

In 1915, Ehrlich fell ill with tuberculosis, a disease that he had likely acquired from his days in Koch’s laboratory. He went to recuperate in Bad Homburg, a spa town famous for its healing carbonic-salt baths. From his room, overlooking the distant plains below, he watched bitterly as his country pitched itself into the First World War. The dye factories that had once supplied his therapeutic chemicals—Bayer and Hoechst among them—were converted to massive producers of chemicals that would be turned into precursors for war gases. One particularly toxic gas was a colorless, blistering liquid produced by reacting the solvent thiodiglycol (a dye intermediate) with boiling hydrochloric acid. The gas’s smell was unmistakable, described alternatively as reminiscent of mustard, burnt garlic, or horseradishes ground on a fire. It came to be known as mustard gas.

On the foggy night of July 12, 1917, two years after Ehrlich’s death, a volley of artillery shells marked with small, yellow crosses rained down on British troops stationed near the small Belgian town of Ypres. The liquid in the bombs quickly vaporized, a “thick, yellowish green cloud²¹⁹ veiling the sky,” as a soldier recalled, then diffused through the cool night air. The men in their barracks and trenches, asleep for the night, awoke to a nauseatingly sharp smell that they would remember for decades to come: the acrid whiff of horseradishes spreading through the chalk fields. Within seconds, soldiers ran for cover, coughing and sneezing in the mud, the blind scrambling among the dead. Mustard gas diffused through leather and rubber, and soaked through layers of cloth. It hung like a toxic mist over the battlefield for days until the dead smelled of mustard. On that night alone, mustard gas injured or killed two thousand soldiers. In a single year, it left thousands dead in its wake.

The acute, short-term effects of nitrogen mustard—the respiratory complications, the burnt skin, the blisters, the blindness—were so amply monstrous that its long-term effects were overlooked. In 1919, a pair of American pathologists²²⁰, Edward and Helen Krumbhaar, analyzed the effects of the Ypres bombing on the few men who had survived it. They found that the survivors had an unusual condition of the bone marrow. The normal blood-forming cells had dried up; the bone marrow, in a bizarre mimicry of the scorched and blasted battlefield, was markedly depleted. The men were anemic and needed transfusions of blood, often up to once a month. They were prone to infections. Their white cell counts often hovered persistently below normal.

In a world less preoccupied with other horrors, this news might have caused a small sensation among cancer doctors. Although evidently poisonous, this chemical had, after all, targeted the bone marrow and wiped out only certain populations of cells—a chemical with specific affinity. But Europe was full of horror stories in 1919, and this seemed no more remarkable than any other. The Krumbhaars published their paper in a second-tier medical journal and it was quickly forgotten in the amnesia of war.

The wartime chemists went back to their labs to devise new chemicals for other battles, and the inheritors of Ehrlich’s legacy went hunting elsewhere for his specific chemicals. They were looking for a magic bullet that would rid the body of cancer, not a toxic gas that would leave its victims half-dead, blind, blistered, and permanently anemic. That their bullet would eventually appear out of that very chemical weapon seemed like a perversion of specific affinity, a ghoulish distortion of Ehrlich’s dream.