Manufacturing depression (9 page)

Ehrlich initially conceived of magic bullets as the body’s own weapons, and of drugs as a means to unleash them, a process he called “chemotherapy.” His investigations into immunology earned him the Nobel Prize in medicine in 1908, but by then his efforts had turned to a more direct use of chemicals: as the bullets themselves.

Ehrlich had also by then gained a corporate patron: Hoechst, to which the magic-bullet model was greatly appealing and which bankrolled Ehrlich starting in 1906. Ehrlich’s a priori approach promised not only huge reward, but also lower research costs. It took some of the guesswork out of drug development by using knowledge about the molecular structure of both drug and pathogen to narrow the
field of candidates. “
There must be
a planned chemical synthesis,” Ehrlich said, and he had an idea of where to start.

The ongoing attempt to synthesize quinine had led researchers to look at other tropical diseases besides malaria, including sleeping sickness, the coma-inducing result of a tsetse fly bite.
In 1903, one of Ehrlich’s dyes
had proven toxic to sleep-sick animals. Trypan red—named after the trypanosomes, the spiral-shaped organisms that caused the disease—proved disappointing as a remedy; whatever it was doing to cure mice was not working in humans. In the course of his work, however, Ehrlich had discovered that trypan red was much more effective in the mice when it was mixed with a form of arsenic. He also heard that a couple of British doctors had used Atoxyl, a compound derived from arsenic, to treat animals infected with sleeping sickness. Atoxyl turned out not to work in humans; even worse, it destroyed their optic nerves, making them blind before they slept themselves to death.

But Ehrlich was intrigued by arsenic, which, like mercury, was an ancient remedy. And
he had discovered something significant
about Atoxyl and other arsenic derivatives: at the end of their chemical chain was a reactive chemical group, an open link of nitrogen and hydrogen that could easily be joined to other molecules. Ehrlich concluded that Atoxyl was effective in animals for exactly this reason: its reactive chemical group latched onto the “parasites” in the same way that dye latched onto tissues. It was perfect, in other words, for the planned syntheses that could both prove out his magic-bullet method and lead to drugs that would make Hoechst happy. And
he determined that the test animals
were doing a little synthesizing themselves: their metabolism converted the arsenic in Atoxyl into a more useful and less toxic compound. Ehrlich decided to follow suit, using the reactive chemical group to make a version of the arsenic metabolite. He combined this molecule with other chemicals, searching for a drug that would work in people.
The first three years
and 417 syntheses were failures, but the 418th attempt found its target:
arsenophenylglycin
, as the compound came to be
known, reliably killed trypanosomes in animals and humans but otherwise left the host’s body alone.

Taken alone, this discovery would probably not have changed the course of medicine. Sleeping sickness, after all, is a rare disease, and one that mostly afflicts people in impoverished parts of the world. But in 1905,
a colleague of Ehrlich’s
at the Charité had discovered another spiral-shaped pathogen, a spirochete, and this one was responsible for a plague that at the turn of the century had infected as much as 10 percent of Europe’s population, ravaging the lives of common folk and kings and artists alike: syphilis.

Known to the French as the disease of Naples, to the Italians as the French disease, to the Russians as the Polish disease, to the Japanese as the Chinese disease, to the English as the Spanish disease, and to all concerned as a scourge, syphilis, or the great pox, first appeared in the late fifteenth century, not long after Christopher Columbus returned from the New World. When Europeans weren’t blaming one another for the disease, they speculated that its true origins were the savages that Columbus and his men met (and then some) on his voyage.

John Hunter, the eighteenth-century British physician, was one of the blame-America-first crowd. He also believed, against the prevailing wisdom of the time, that syphilis was caused by a
“putrid liquid”
contained in the pus that exuded from a chancre. In 1767,
he injected some of that liquid
, obtained from a patient’s penis, into his own. His intent was to determine whether gonorrhea and syphilis were variants of one illness. He didn’t consider the possibility that his patient could have both illnesses, so when he developed symptoms of each, he concluded that “
gonorrhea and the chancre
are the effects of the same poison.” Even if he had this wrong, however, he did manage to report accurately on the natural course of venereal diseases—although
when his aorta burst
twenty-six years later, he probably didn’t know that his experiment had killed him.

Hunter treated himself
by cauterizing and applying mercury to his chancres and to the sores that erupted elsewhere in the disease’s
later stages.
Mercury had been the treatment of choice
for the pox from the beginning—probably because physicians since Galen had used it with some success to heal skin conditions. Doctors rubbed mercury on patients’ genitals, injected it into their veins, vaporized it so they could breathe in the vapors, served it up as a chewing gum, dissolved it into alcohol to be imbibed, infused it into their rectums, and even, at least in Italy, coated their underpants with it. (The treatment gave rise to a rueful adage: “
A night with Venus
is followed by a year with Mercury.”) Mercury did seem to have some effect, and physicians learned to recognize the symptoms of mercury poisoning, like salivation, before it killed their patients, but
doctors’ ability to publicize
themselves as healers of the pox, which they did in slick pamphlets promising effectiveness and discretion, generally far surpassed their ability to actually do so.

With the success of the smallpox inoculation, some nineteenth-century doctors thought that the great pox would also be controlled by vaccine, but they soon found that infected people could get reinfected, making the disease unsuitable for that treatment.
Public health measures
also foundered—on both the distaste for talking openly about sex and on the near impossibility of controlling people’s sexual behavior. By midcentury, at least one doctor saw syphilis as making a mockery of progress.

Nineteenth century man
has managed to do away with long distances, tunnel through mountains, harness the power of fire, and yet he has not thus far managed to preserve himself against disease. As a conqueror of matter, a new Icarus, he sets out boldly heavenwards; as the threadbare king of creation he…falls prey to a disease which the simplest precautions would enable him to avoid.

And in 1875,
a French scientist gave even more reason
for concern: syphilis, he said, was even worse than already thought, for it not only caused the genital chancres of its primary stages, and the blisters
and fevers of its secondary stages, but a third, more horrifying stage, characterized by tabes dorsalis, a condition that caused people to lose muscle control and balance, and general paresis, a form of insanity. By one count, nearly half of the patients in Europe’s mental hospitals were suffering from tertiary syphilis.

A pale spiral-shaped organism had been spotted in chancres as early as 1837. But it was hard to make out in the microscopes of the time, and germ theory was still a twinkle in Pasteur’s eye, so there was little interest in isolating and identifying the bug until Ehrlich’s colleagues found it in blood and tissues as well as syphilitic sores. Because it vaguely resembled the spiraling trypanosomes, it made sense to see whether compound 418, which had killed those germs so well, would also attack the syphilis spirochete. The answer, unfortunately, was no, but Ehrlich and Hoechst were convinced that they were on the right track, and eventually Ehrlich’s 606th compound did the trick, killing the syphilis bug in infected rabbits.

Even before Ehrlich had satisfied himself that his results were not a fluke,
word about 606 got out
—and so, thanks to Hoechst, did samples of the drug. Doctors in Italy and Russia reported good results with early stage syphilitics, a Swiss physician reported that in addition to successful treatment of syphilitics he’d used 606 to cure a case of leukemia, and Alexander Fleming, a British doctor not yet famous for stumbling onto penicillin, reported that the drug had a “
remarkable effect
” on syphilis.

In April 1910, Ehrlich officially announced his success at a Wiesbaden medical conference. Almost immediately, he was besieged with requests for 606.
Patients showed up
at his research offices, hoping for a shot. By September, more than ten thousand patients had been treated, a number that had tripled by November. By year’s end
Hoechst had distributed 65,500 free doses
to doctors all over the world—virtually everywhere but the United States, where doctors warned that having a cure for the disease might encourage promiscuity. Headlines soon trumpeted the success of Salvarsan, the household-friendly name Hoechst settled on instead of 606 or the
even less mellifluous
dihydroxydiaminoarsenobenzene
. By year’s end the company had put more than
375,000 doses
into the pharmacies and was the proud owner of the world’s first scientifically proven wonder drug—a magic bullet aimed directly at the heart of one of the worst diseases known to humankind.

Shortly after Salvarsan’s release, a German magazine ran an article that included this clever encomium to the drug:

There’s hardly a child
who believes in the gods,

They’ve vanished without a trace;

Even those who serve at Venus’s court

Now laugh in Mercury’s face.

This enthusiasm was misplaced, as wonder drug enthusiasm often is. Salvarsan promised to make the world safe for adultery and fornication, but even in successful cases, treatment could drag on for months or years of repeated, painful injections and debilitating side effects. Sometimes it made people sick or even killed them—it was, after all, made from arsenic. Some doctors stopped laughing at Mercury and started augmenting Salvarsan with old-fashioned quicksilver ointments. The treatment ultimately came to be seen, as one doctor put it, as “a
long, slow, painful, and expensive grind
,” and the world’s enthusiasm, at least when it came to syphilis treatments, eventually moved on to the next wonder drug, Fleming’s penicillin.

But the quatrain’s optimism was, in another sense, spot-on. Salvarsan finished the job that Hippocrates started. After two millennia of stumbling around in the humoral darkness, doctors and drug companies were ready to displace the gods entirely from the clinic by taking direct aim at disease and killing it at its source. And even if the drug itself was only a qualified success, the idea behind it was a blockbuster. Soon enough, Ehrlich’s magic-bullet promises came true in ways that exceeded imagination.

To cite just three familiar examples: scientists identified the lack of insulin as the culprit in diabetes in 1921; in 1922 a team in Toronto successfully treated a fourteen-year-old diabetic boy; and in that same year Eli Lilly and Company devised a method for mass-producing human-ready insulin from the pancreas of a cow. In 1942, chemists at Charles Pfizer and Company, which made its first fortune by producing citric acid, figured out a way to grow penicillin in fermenting corn liquor, allowing a drug previously great in promise but short in supply to be mass manufactured in time to treat the wounds (and syphilis) of World War II soldiers. In the late 1950s, researchers at Merck discovered that chlorothiazide, another benzene compound, could change blood chemistry enough to lower blood pressure, and Diuril was born. By the turn of the twenty-first century, Oliver Wendell Holmes’s prophecy had come true, but in a way he couldn’t have expected: the fishes were indeed suffering from the modern
materia medica,
but only because millions of people living better through chemistry were flushing the metabolized remains (and unused pills) down the toilet and out into the sea.

It is nearly impossible to overstate the impact of Ehrlich’s idea. It has turned the suppliers of magic bullets into wealthy and powerful corporations, and doctors into dead-aim gunslingers possessed of an authority that Hippocrates could only dream of. It has also turned diseases into afflictions with specific causes that can be located in our biochemistry. By revolutionizing our view of sickness and health, in short, it has ushered in a new climate of opinion about suffering and its remedy, and even more about who we are and why we suffer: not the descendants of Job, awaiting the next inexplicable misery, but people with a biochemical essence that can be known and, when it goes wrong, corrected.

And that’s not all. If scientists can figure out how to make a beautiful color the first time, every time—and out of industrial waste no less, no mucking about with snails or bats—and use that knowledge not only to make the ladies of Paris happy but also to
cure the great pox, then the prospects for humankind are suddenly and dramatically enhanced. Petitioning Yahweh for an account of the wherefores of suffering—and falling into resignation or despair when no answers are forthcoming—is unnecessary when doctors can peer into the recesses of the body, find the answers in its molecules, and send the chemicals in to the rescue. The promise of a boundless future that originated with the Enlightenment and began to come to fruit in the Industrial Revolution has perhaps no better expression than in the birth of scientific medicine.

But that promise also created a temptation, one that eventually would prove irresistible. To the manufacturers of drugs, diseases are markets. The continued growth and success of the pharmaceutical industry depends on a proliferation of those markets. It was only a matter of time before doctors and drug companies started to improve upon nature in yet another way: by creating the diseases for which their potions are the cures.