There was, however, one big, unavoidable problem with chemical synthesis: Optical microscopes could make cells an object of study for the biologists like Pasteur and Koch, who used them to establish the precepts of the germ theory. But the molecules that are central to all chemical activity couldn’t be seen by even the most powerful lenses.* Because molecules aren’t perceptible to the eye, building one in a laboratory was a little like trying to build a scale model of the Eiffel Tower while wearing a blindfold.
Luckily, it’s not quite as daunting as that. There are a number of rules that determine how elements bond to, and react with, one another—the equivalent of understanding which bolt attaches to a particular nut in the overall construction of the Eiffel Tower. The ways in which acidic substances like hydrochloric acid react with alkaline ones, such as lye, were intuited as far back as Lavoisier (although he got almost all the elements involved wrong). In 1857, August Kekulé, a German organic chemist, discovered a concept about chemical structure that first-year chemistry students learn as an atom’s valence (Kekulé and his contemporaries called them “affinity units” or “combining power”). Different elements, he proposed, have distinct powers of combination, and can bond (or share an electron) with other elements based on their combining powers. If the power was one, as with hydrogen, the atom could form only a single bond; for a combining power of two, such as oxygen, either two single bonds or one double bond; and for a power of three, nitrogen, for example, either three single bonds, a double bond and a single bond, or one triple bond. Twelve years later, a Russian chemist named Dimitri Mendeleev published the first of his periodic tables, then containing sixty-five named elements, organized by atomic weight and valence. Though it wasn’t until 1897 that J. J. Thomson discovered the electron (and another nineteen years would pass before their essential role in bonding was recognized), from a practical standpoint, chemists knew the rules of bonding one atom to another.
With the discovery of electrons, though, a huge suite of different chemical reactions could now be explained: reduction reactions, in which electrons are gained, and oxidation reactions, where they are lost; acid-base reactions, mediated by charged particles—ions—where positive protons seek out negative electrons in base molecules. As a result, the chemistry that Paul Ehrlich was able to teach himself was sophisticated enough that he could perform experiments on extraordinarily complex chemical structures.
As far back as the mid-1880s, Ehrlich had experimented with the use of azo dyes*—these are aniline derivatives with names like methylene yellow, congo red, and alizarin yellow—as potential therapeutic agents. About 1891, he identified a variant of the dye methylene blue* as a treatment for malaria—a distinctly mediocre treatment. First, the compound was only mildly effective; also, due to its origins as a coloring agent, it turned urine green and the whites of the eyes blue, which understandably limited its appeal to both patients and physicians. Even with its problems, though, the dye-based treatment was effective enough that methylene blue pills remained a first-line antimalarial drug well into the 1940s, and promising enough to encourage Ehrlich in the search for his Zauberkugel.
He had, by then, learned that testing a magic bullet required a fairly easy-to-hit target, and believed he had found one in trypanosomiasis, the “sleeping sickness” caused by the introduction of trypanosomes into the bloodstream of infected animals, generally by the bite of the tsetse fly. The disease seemed perfect: first, because the trypanosomes that cause it are giants of the microbial world (they’re protozoans: parasites that, like bacteria, have a single cell, but which also have nuclei and some other cellular machinery), they are relatively easy to see and identify; and second, because it was a reliable killer of the most prolific lab animals, white mice. In 1903, Ehrlich had synthesized his own azo dye as a potential cure. Named trypan red in honor of its intended target, it followed a frustrating but common course: early success, followed by long-term failure. It didn’t kill all versions of the protozoan, which made it functionally useless.
But not without providing useful data about the next step. In 1863, the French chemist (and one of Pasteur’s many rivals) Antoine Béchamp had discovered an arsenic-based compound he had named atoxyl; some recently published experiments indicated that atoxyl killed trypanosomes. In 1905, Ehrlich’s by then well-cultivated talent for visualizing molecular structure resulted in a remarkable insight: The structure of atoxyl was not that of a chemically deactivated, or stable anilide, but of a far more changeable arsonic acid. The significance was huge: He could try to induce a chemical reaction from an anilide for years without getting any more response out of it than he would by hitting a steel girder with a rubber hammer. An arsonic acid, however, was chemically reactive. As his colleague Alfred Bertheim would later write, “Probably for the first time, therefore, a biologically effective substance existed whose structure was not only known precisely but also . . . was of a simple composition and extraordinary reactivity, which permitted a wide variety of modifications” [emphasis added]. In 1907, Ehrlich began tinkering with the molecule’s promisingly unstable structure. He would continue tinkering for three years.
When he was asked, later in life, to describe his experimental strategy, Ehrlich responded with the ponderous “uniform direction of research combined with as much independence as possible for individual researchers.” (It is even more ponderous in German: Einheitliche Richtung der Forschung bei möglichst selbständigen Leistungen der Einzelnen.) This sounds a bit more democratic than was actually the case; most of his subordinates recall a lot more uniformity of direction than independence; one of them remembered vividly that Ehrlich “often hammered on the anvil of his assistant’s brains.” However perceived at the time, it seems unarguable that among Ehrlich’s many gifts as a scientist, his ability to organize the work of dozens of subordinates stood out. He had consciously adopted the same management style that had been pioneered by the synthetic dye industry, in which a prominent research director, Heinrich Caro, likened the process of testing new compounds to an “endless combination game [utilizing] scientific mass-labor.”
The atoxyl experiments were among the very first in biology to apply these principles; to take a compound whose structure resembled other molecules that exhibited at least some of the desired effect (the term of art is “lead compound”) and modify its chemical structure in a systematic and methodical way in order to optimize that effect. Though finding a promising compound like the organoarsenic atoxyl is good fortune, modifying it successfully depends on a conscious and deliberate strategy. Ehrlich’s was driven by his belief in the side-chain receptor theory, which demonstrated that the action of any substance, helpful or harmful, was entirely a matter of chemical affinity: the right lock-and-key combination.
The goal was at the intersection of helpfulness and harm: Anything powerful enough to have an effect is virtually certain to have more than one. If it can kill a pathogen, it can kill (or at least damage) a host. The goal of the atoxyl experiments was to increase the damage the compound could inflict on the pathogen, while reducing its impact on the host. Ehrlich’s hypothesis, based on long chemical experience with both medicines and aniline dyes, was that substituting different amine groups—the simple nitrogen-based structures that attached themselves to atoxyl’s central ring like a kickstand on a bicycle—could lower toxicity to the host. One group of researchers in Ehrlich’s lab busied themselves with finding just such an amine structure.
The other goal was increasing atoxyl’s firepower against pathogens; a task made even more difficult because it wasn’t clear where the firepower came from in the first place. Ehrlich postulated that what made atoxyl toxic to trypanosomes was not arsenic per se, but a particular arsenic radical: an atom with an unpaired electron in its outer shell. Ehrlich asked Bertheim to test this particular hypothesis by dumping electrons into, or reducing, atoxyl in the lab.* The one Ehrlich had his eye on was trivalent arsenic, one with three bonds and an electron in its oute
r shell. However, in a test tube, atoxyl was pentavalent, with five bonds to arsenic in its outer shell. It was also harmless. Somehow, the host organism itself was changing the structure of the arsenic, reducing the number of free electrons. This gave the lab’s other team its task: hastening the reducing process that turned pentavalent arsenic into trivalent.
This sounds more rational than it actually was. The nice name for the approach is trial and error: brute force. Each of the new compounds, with increased amounts of trivalent arsenic, and different substitute compounds in the amine group, was tried out on test animals all over Europe.
Small wonder that the approach worked slowly. But it did work. It wasn’t until arsenophenylglycine, known internally as Compound 418, was tested in 1909 that Ehrlich and his colleague, the Japanese bacteriologist Sahachirō Hata, found any real success, and it was decidedly mixed. Compound 418 cured sleeping sickness, but came with significant side effects, including an unfortunate habit of causing blindness in a small percentage of the animals on which it was tested.
On August 31, 1910, the lab hit the jackpot. Compound 606: arsphenamine.
Arsphenamine was not, as most histories have it, the 606th compound synthesized. Ehrlich’s lab had been working hard, but not that hard. Hoechst’s naming convention used the first digit to refer to a particular experimental compound, and the following numbers to denote a specific variant, which made arsphenamine the sixth version of the sixth compound. Because different compounds were being tested simultaneously, 606 had actually been synthesized for the first time in 1907, before number 418, which was the eighteenth version of the fourth compound.
Normally, variants that underperformed would have been discarded; and, indeed, Ehrlich’s lab had moved on after the first tests of 606. The reason the lab returned to a compound discovered years earlier was the accidental discovery that arsphenamine didn’t kill only trypanosomes. Because Ehrlich thought, mistakenly, that trypanosomes caused syphilis, he had tested the drug on a wide range of syphilitic animals as well, recruiting collaborators from all over the world, including Kitasato Shibasaburo, since returned to Tokyo, and Albert Neisser, in what was then the Dutch East Indies, to test versions on rabbits, monkeys, and apes. Compound 606 cured them, too.
For good sound business reasons, this made arsphenamine far more interesting to a European chemical company. Sleeping sickness was a disease of what was not yet known as the Third World. Syphilis, on the other hand, had been killing and disabling Europeans for centuries. Though epidemiological historians continue to debate whether the disease was already present in Europe before explorers brought it back from the New World at the end of the fifteenth century, there’s no doubt that it was one of the best-known and feared diseases in Europe from 1495 onward, causing everything from the characteristic genital sores, to painful abscesses, to destruction of the nervous system, to death. In 1520, the great humanist philosopher and poet Desiderius Erasmus called it “. . . the most destructive of all diseases,” asking, “What contagion does thus invade the whole body, so much resist medical art, becomes inoculated so readily, and so cruelly tortures the patient?”
To ask the question was to answer it. Attempts to treat syphilis were either useless—the resin from the Caribbean “holy wood” known as guaiacum—or nearly as dangerous as the disease itself—mercury in its various forms, whose predictable side effects included mouth ulcers, loss of teeth, and even death, particularly since treatments could go on for years.* And, since blocking the route of transmission for the “great pox”—almost always sexual contact—was as problematic as asking people to stop breathing, syphilis was a terror for centuries before the organism that caused it was identified: the corkscrew-shaped bacterium Treponema pallidum.
A terror for some, an opportunity for others. With hundreds of thousands if not millions of men and women in the world’s wealthiest countries acquiring syphilis every year, a cure looked like a very profitable item for the company that could manufacture it in quantity.
By the first years of the twentieth century, the German chemical industry was a patchwork of partnerships and cooperative marketing arrangements—in German, Interessengemeinschaft, or “communities of interest.” All of them were profitable, but like all profitable enterprises eager to become more so. One group was dominated by Agfa (Aktiengesellschaft für Anilinfabrikation, or the Aniline Manufacturing Corporation) and BASF (Badische Anilin-und Soda-Fabrik, or Baden Aniline and Soda Manufacturing). Another consisted of Hoechst AG—the same company where Behring had managed to exclude Ehrlich from participation in the profits from the diphtheria antitoxin—and Cassella Manufacturing.
The motto of Ehrlich’s lab was Geduld, Geschick, Glück, und Geld—patience, skill, luck, money. Paying dozens of researchers to synthesize and test hundreds of potential molecules over the course of years isn’t cheap. That’s why the most significant innovation of the great German biochemical revolution was neither drugs nor vaccines themselves, but the creation of a durable funding source for ongoing lab research. Cassella had invested thousands of marks in Ehrlich’s research—far more, even accounting for inflation, than Napoleon III had provided to Pasteur—and supplied dozens of different chemical compounds customized to Ehrlich’s specifications, all in return for a share in any subsequent patents. This, even more than the drugs themselves, was new. It was also more than a little controversial, at least within the great chemical corporations, which had grown profitable on dyes and fertilizers rather than drugs. Ehrlich argued strenuously that it was also necessary, writing in 1908, “The material and mental support of our chemical factories is largely indispensable for modern therapeutics, and it would therefore not be advisable to loosen this natural union.” In 1910, the “natural union” paid off. Cassella’s partners at Hoechst AG introduced arsphenamine under the trade name Salvarsan. It was the world’s first synthetic chemotherapeutic agent.
Salvarsan was a huge success, within a year of its introduction the most widely prescribed drug in the world. It was also one of the most challenging, for both doctors and patients. Common side effects included nausea and vomiting. Storage of the compound was a tricky business, requiring vials tightly sealed to avoid oxidation. Treatment entailed weekly injections of the highly diluted compound over the course of a year—very highly diluted; each injection required at least 600 cc of solution per injection, or a pint and a quarter of solvent pumped into a patient’s body with every visit to the doctor. Many doctors decided to experiment with different solvents; others to try different injection locations: into the muscle, under the skin, or directly into the bloodstream. Intramuscular and subcutaneous injections tended to be painful; intravenous ones still unfamiliar to physicians, and therefore risky. The dangers of such a regimen, given the needles and syringes available in the first decade of the twentieth century, were very real: Too much seepage from the injection site could result in amputation or even death. Moreover, as would become a familiar theme of every subsequent advance in drug therapy, it was widely used for ailments well outside its arena of effectiveness. In some unfortunate cases, it resulted in death from cerebral hemorrhage. In 1912, Hoechst, Ehrlich, and Hata responded with a new and improved version, marketed as Neosalvarsan, which was soluble in water, and less toxic to boot. Like its precursor, it was a blockbuster: a miracle drug.
Even a century after its introduction, the structure of Salvarsan remained unknown; that is, though the formula for Salvarsan is well known, Ehrlich’s lab never did establish the precise structure of the compound. They originally synthesized it by a very delicate chemical process* that tended to introduce impurities that could affect the compound’s toxicity and/or efficacy dramatically. The actual structure of Salvarsan, which wasn’t discovered until 2005, consists of mixtures of cyclic molecules, which prompted some people to suggest that it wasn’t a Zauberkugel, but Zauberschrot: a magic buckshot. Even more mysteriously: As of this writing, no one has yet figured out the mechanism by which Salv
arsan and Neosalvarsan target T. pallidum so precisely.
The precision of the arsphenamines is one reason that, while Ehrlich’s achievement looms as large as any in the history of medicine, it was also a false start. Though it would remain the most important drug in the medical arsenal for decades, it was too narrowly effective to revolutionize the practice of medicine all by itself. The few attempts that followed in its wake were notably less successful; Ehrlich himself developed another compound intended to cure streptococcal pneumonia. However, while optochin (also known as ethylhydrocupreine hydrochloride) is indeed toxic to the strep bacteria, it is nearly as dangerous to humans, in whom it frequently causes irreversible blindness. Today it is used, like Koch’s tuberculin, as a diagnostic tool to identify the presence of Streptococcus pneumoniae rather than a therapy.
Nonetheless, Salvarsan marked as huge a step on the way to the birth of the antibiotic age as the germ theory itself. The power of a well-financed mass attack on disease had been demonstrated. It might very likely have provided the template for a true therapeutic revolution even before Ehrlich’s death in 1915, had Europe not chosen that very moment to destroy itself in the most violent war in the history of Western civilization.
—
Within a week of the assassination of the heir to the throne of the Austro-Hungarian Empire in Sarajevo, France and Germany had declared war on one another, troops of the Dual Monarchy were shelling Belgrade, Tsar Alexander had mobilized the armies of the Russian Empire, Kaiser Wilhelm’s army had invaded Belgium, and Great Britain had declared war on Germany. Europeans would spend the next four years killing, maiming, poisoning, and starving one another.
This grim future was unknown to the Russians, French, Germans, Austrians, and Britons who applauded the start of hostilities, each convinced that a rapid and painless victory was theirs for the taking. Two months later, the cheering hadn’t quite stopped, but it probably should have. During the first eight weeks of combat on what came to be known as the western front, the armies of the German Empire had suffered 550,000 casualties; those of the Republic of France 590,000. At the first Battle of Ypres alone, which bloodied the fields of Flanders for five gory weeks, from the nineteenth of October to the twenty-second of November 1914, 85,000 French and 56,000 British soldiers were either killed or wounded, virtually destroying the relatively small British Expeditionary Force. On the other side, more than 18,000 German soldiers were listed killed or missing, and more than 29,000 wounded.
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