Even so, that explains American postwar dominance a whole lot better than the achievements that occurred during the war. Germany possessed an enormous head start in the key industries of drug development and production, was preeminent not only in every aspect of chemical manufacturing, but also benefited from hundreds of alliances between commercial enterprises like the I. G. Farben cartel and what were, at the outbreak of the war, still the world’s most prestigious universities. Moreover, once the Oxford group started publishing in 1940, academic papers about penicillin started appearing practically every week in both English and German, which means that however much the OSRD and Britain’s Medical Research Council tried to keep the details secret, by 1942 the Penicillium cat was out of the bag. And yet, even by 1945, Germany was able to produce only about 30 grams of penicillin a month, no more than the quantity required to treat four dozen or so patients. Germany, where both Salvarsan and Prontosil were introduced, had become a dead end in the search for more powerful anti-infective treatments.
The reason certainly wasn’t because the Nazi state lacked an urgent need for treating battlefield injuries. In May 1943, when the OSRD and the War Production Board approved an additional sixteen new plants for producing the penicillin needed for D-day, thirty thousand soldiers of the Wehrmacht died on the eastern front alone, a huge number from septic wounds.
So far as can be gleaned from the historical record, the answer is not primarily, “They were manufacturing Zyklon B for the gas chambers instead.” Mass killing on an industrial scale was, indeed, a national priority for the Nazi state; but, for Germany’s great chemical companies, an even higher priority was oil. The Saar region had enough coal to fuel the Industrial Revolution, and more than enough to run German factories. Oil, though, particularly petroleum, was a different matter. Outside of Romania, there wasn’t a decent-sized oil field anywhere from the Atlantic to the Urals. Which was why, even before the Nazis took power in 1933, I. G. Farben was investing enormous resources in the manufacture of synthetic fuels: $100 million and $125 million in current dollars between 1925 and 1932, or at least $1.7 billion today.
It wasn’t, by traditional standards, a profitable investment. The Leuna brand of synthetic gasoline—the name came from the facility where it was produced, in the Saxon city of Leuna, near Leipzig—was an attempt to gasify Germany’s still-abundant reserves of coal, using the chemical process known as hydrogenation. Even with substantial subsidies from the Weimar government, though, it hemorrhaged red ink from 1930 forward, and continued to do so after the Nazis took power in 1933. Carl Bosch, the Nobel Prize–winning head of BASF and, since the 1925 merger, a director of I. G. Farben, instructed his staff to provide documentation for even larger state subsidies, projecting that the German state would consume 50 percent more fuel oil and petroleum by 1937. Bosch’s protégé and successor, Carl Krauch—a Nazi Party member, unlike his anti-Nazi boss—proposed to Hitler’s cabinet that domestic production of fuel oil and petroleum could be increased between 25 and 63 percent, from 500,000 tons to nearly 3 million tons annually. If, that is, the national government could close the German market to “foreign influences” and agree to buy the fuel at a substantial premium over the world market price.
What this meant, in effect, was that the Nazi state would be subsidizing the production of oil to the extent that nearly 40 percent of all industrial investment in Germany before 1939 (except for coal and electricity) went to either synthetic oil or—the other requirement of a mechanized army—synthetic rubber.
It was a success, if that’s the correct word, for I. G. Farben. Revenues soared, at least partly due to a gruesome policy for controlling labor costs: Dozens of Farben’s directors would serve time as war criminals for employing slave labor in its synthetic oil and rubber plants. Scholven AG, a joint venture with a number of German mining companies, produced 125,000 tons of synthetic fuel in 1936; by August 1939, just before the start of the Second World War, I. G. Farben had twelve hydrogenation plants making gasoline and other refined oil products, for which they earned between $65 million and $140 million annually—up to $1.5 billion in current dollars. Another $50 million was earned annually producing synthetic rubber.
This also guaranteed, though, that tens of millions of dollars weren’t being spent subsidizing research into any drugs, much less penicillin. Perversely enough, pharmaceutical companies in the United States and the United Kingdom, fearful of investing in factories that could be made obsolete so quickly, diverted millions of dollars from a technology that actually worked—fermentation—in an attempt to surpass Germany’s perceived mastery in chemical synthesis. And they did so while the Germans were embarked on an entirely different project. The country that had the world’s best chemists in the 1930s directed them to spend the decade—and a ridiculously large percentage of the nation’s investment capital—not in pharmaceutical innovation, but in supplying fuel to the Wehrmacht. The big difference was that the United States was wealthy enough to afford to make expensive mistakes. Germany wasn’t.
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In 1943, British production of penicillin had been approximately equal to that of the United States. In 1944, it was barely one-fortieth as large.
Howard Florey, more responsible than anyone for that extraordinary achievement, spent most of 1943 and 1944 in the field, investigating how best to use penicillin for treating battlefield injuries. On a trip to his native Australia, he gave forty-two lectures on the proper use of the drug, and would eventually train five hundred clinicians and more than two hundred pathologists on penicillin therapy.* He also demonstrated the effectiveness of penicillin in treating gonorrhea, which was believed to be at least as dangerous to Allied troops as German artillery. One of the largest grants from the CMR during the months leading up to D-day had been to research the best ways to use penicillin to help treat gonorrhea—one American administrator noted that “the goal [is] to make penicillin so cheaply that it costs less to cure [VD] than to get it . . .”—thus keeping tens of thousands of troops at least putatively battle ready (though also creating an ethical dilemma about treating civilians in postwar Europe in preference to STD-infected soldiers).
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By December 1945, when Florey, along with Alexander Fleming and Ernst Chain, received the Nobel Prize in Physiology or Medicine, penicillin had already saved tens—perhaps hundreds—of thousands of lives. But it transformed the world in other ways, too. The penicillin project had created an entire industry, and built what would become some of the most profitable companies in history: not merely the American participants in the penicillin project, but also British firms like Glaxo, France’s Rhône-Poulenc, and even Swiss companies like CIBA-Geigy and Sandoz. At the Nobel Banquet, Professor A. H. T. Theorell of the Nobel Institute of Medicine toasted the laureates thus:
To you, Ernst Chain, Howard Florey, and Alexander Fleming, I will relate one of Grimm’s fairy-tales, that I heard as a child. A poor student heard under an oak a wailing voice that begged to be set free. He began to dig at the root, and found there a corked bottle with a little frog in it. It was this frog that wanted so badly to be set at liberty. The student pulled the cork, and out came a mighty spirit, who by way of thanks for the help gave him a wonderful plaster [i.e., bandage]. With the one side, one could heal all sores; with the other one could turn iron into silver. . . .
Florey, Chain, and Fleming, along with a long list of colleagues, hadn’t quite healed all sores with their discovery. Penicillin was widely, but not universally, effective; it had no curative powers against infectious diseases caused either by viruses or by Gram-negative bacteria. But for institutions like Merck, Pfizer, Squibb, and all the others, it had indeed turned iron into huge quantities of silver. The first antibiotic, and its successors, would do so for many decades to come.
SIX
“Man of the Soil”
In November 1915, Goodhue County, Minnesota, opened the Mineral Springs Sanatorium (“for consumptiv
es”) at Cannon Falls, a small town about thirty-five miles south of Minneapolis. Mineral Springs had only thirty-four beds when it opened, a small hospital, even by the standards of the rural Midwest. Forty years later, the number of beds had increased, but the disease that filled them, year in and year out, was always the same: the “white plague”—pulmonary tuberculosis.
One of those beds, in October 1945, was occupied by a twenty-one-year-old woman believed to be days away from death. It’s unknown how she contracted pulmonary tuberculosis, but the overwhelming likelihood is that she breathed in aerosol droplets that had previously occupied the respiratory tract of another infected person. Perhaps that person sneezed, or coughed, or just exhaled. It didn’t matter; while a sneeze can transfer a million cells of the bacterium known as Mycobacterium tuberculosis, ten is all it takes to start a colony. The young woman, Patricia Thomas, had definitely been colonized. She had endured months of high fever, loss of appetite, weight loss, muscle atrophy, and the disease’s chronic, blood-tinged cough.
In the year of her hospitalization, seventy-five thousand Americans would be killed by the deadliest infectious disease in history. By then, tuberculosis had killed one-seventh of all the humans who had ever lived: more than fifteen billion people.
That much devastation leaves a trail. Skeletons exhumed from Egyptian gravesites more than four thousand years old have the characteristic deformities of Pott’s disease, or spinal tuberculosis, as do skeletons from Neolithic sites in northern Europe and the Mideast. Almost from the moment human civilizations began to record the stories of their lives, tuberculosis was a featured player, generally appearing in the last chapter. Assyrian clay tablets describe victims coughing blood before they died. Hippocrates treated patients wasting away with chest pain and drowning in bloody sputum. Ancient Chinese physicians called the disease xulao bing; Europeans, consumption. Recommended treatments had included insect blood, breast milk, bloodletting, high-altitude living, sea travel, drinking wine, avoiding wine, and—most famously—the “king’s touch,” which was the belief that a divinely sanctioned monarch, such as the king of England or France, could, by a laying on of hands, cure what they knew as scrofula.*
However, the recorded history of tuberculosis is only the last part of its story. For a long time, the accepted wisdom was that tuberculosis emerged around the same time that humans discovered agriculture and started forming settled communities, during the so-called Neolithic Demographic Transition, or NDT, which began some ten to twelve thousand years ago. The reason that medical historians assumed this for so long has to do with the complicated nature of tuberculosis itself. Most of the really scary infectious diseases are what demographers call “crowd diseases.” Crowd diseases tend to feature high mortality—up to 50 percent when untreated—and a very rapid means of transmission. From an evolutionary perspective, the two go hand in hand; pathogens that kill their hosts need to spread rapidly, or die out. Most crowd diseases are known to have emerged around the time of the NDT, when Homo sapiens not only experienced a rapid population explosion but an even faster increase in population density. Villages and cities, where people and domestic animals lived in far closer quarters than the nomadic hunter-gatherer societies they succeeded, created a target-rich environment for crowd disease pathogens. For that reason, a large number of crowd diseases started as zoonoses: animal diseases that were able to jump to human hosts.
But while tuberculosis is both highly dangerous and very easily spread, it also has the characteristic features of chronic, noncrowd diseases, the ones caused by pathogens that thrived in the low-density societies that preceded the NDT. Most such pathogens were not originally zoonotic, and are typically able to lie dormant within a host for years, only to be reactivated when opportunity presents. Treponema pallidum, the bacterium that causes syphilis, is a famous example, as is Borrelia burgdorferi, the bacterium behind Lyme disease. Another is Mycobacterium leprae, which is the causative agent for leprosy; and predictably enough, so is its cousin, M. tuberculosis. One implication of this fact is that tuberculosis is not, as once was thought, a disease that jumped from domestic animals to humans. Since it’s older than domestication, it’s far likelier that humans originally gave it—the version that is now known as M. bovis—to farm animals, rather than the other way around. It certainly appeared in human populations long before our ancestors first experimented with animal husbandry. Decades after Patricia Thomas encountered M. tuberculosis, genetic analyses of hundreds of different strains of the bacterium decided the issue: The pathogen had originated in Africa, somewhere between forty and seventy thousand years ago.
In the same way that H. sapiens dispersed, evolved, and expanded, so too did M. tuberculosis: from Mesopotamia eight to ten thousand years ago, to China and the Indus valley a few thousand years later, eventually to Europe and the New World. It didn’t, of course, stop there. M. tuberculosis experienced another evolutionary burst only a few centuries ago. The most successful modern lineage—the so-called Beijing lineage—experienced a population increase over the last two centuries almost exactly paralleling the sextupling of human population during the same span.
A population of pathogenic bacteria that seemed always to be growing larger was bad news for its human hosts. But it wasn’t quite bad enough. As the pathogen was increasing its numbers, it was also evolving new and deadly virulence factors, which is one reason that Patricia Thomas was dying in her hospital bed. Though M. tuberculosis has been, by the standards of bacteria, an extremely slow-evolving and stable organism—the ubiquitous bacterium known as E. coli divides and replicates about once every twenty minutes, while M. tuberculosis does so only every fifteen to twenty hours, which means that spreading an evolutionary adaptation through a population takes fifty times as long. The small portions of its genome that do mutate almost always increase its virulence.
Even today, tuberculosis virulence isn’t fully understood. However, it is known that unlike most pathogens, including the strep bacterium that nearly killed Anne Miller,* M. tuberculosis doesn’t produce toxins. Instead, the microbe is ridiculously efficient at hijacking the host’s own defenses and transforming them into deadly attackers. Any time the host’s immune alarm bells go off, it summons macrophages, the oversized white blood cells, to the site of infection. The macrophages, whose job it is to engulf and digest foreign objects, form cavities: vacuoles known as phagosomes that surround the invading pathogens. Once surrounded, the macrophage then connects the phagosome to the lysosome, a chemical wood chipper that uses more than fifty different enzymes, toxic peptides, and reactive oxygen and nitrogen compounds that can, in theory, turn any organic molecule into mush.
When they attempt this with M. tuberculosis, however, things don’t work out as planned. The bacterium secretes a protein that modifies the phagosome membrane so it can’t fuse with the lysosome. Thus protected, it is able to transform the macrophage from an execution chamber to a comfortable home—one with a well-stocked larder, since another of the pathogen’s talents is the ability to shift from dining on mostly carbohydrates (which is what it eats when grown in a Petri dish) to consuming fatty acids, particularly the cholesterol that is a common component of human cell membranes.
It’s the replication that matters. Within three to eight weeks after breathing an aerosol containing a few hundred M. tuberculosis bacteria, the host’s lymphatic system carries them to the alveoli of the lungs: the tiny air sacs where carbon dioxide is exchanged for oxygen. As M. tuberculosis forms its colonies inside macrophages, they create lesions: calcified areas of the lung and lymph node. Some burst; others form a granuloma—a picket fence of macrophages—around the colony. Within three months, the interior of the granuloma necrotizes, that is, undergoes cellular death. Some of the deaths occur within the lungs, leading to the painful inflammation known as pleurisy, which can last for months. Other infested areas, known as tubercles, break off from the lungs and travel via the bloodstream to other parts of the body, bec
oming the frequently fatal form of the disease that physicians know as extrapulmonary tuberculosis—Patricia Thomas’s diagnosis. When it settles in the skeletal system, it can cause excruciatingly painful lesions in bones and joints. When it lands in the central nervous system, as tubercular meningitis, it causes the swelling known as hydrocephalus; on the skin, where it’s known as lupus vulgaris, it leaves tender and disfiguring nodules.
And, even when the body’s determined immune system destroys most of the granulomas, they leave behind huge amounts of scar tissue, which weaken the host’s ability to breathe. Bronchial passages are permanently blocked. Frequently, the cells needed for oxygen uptake are so damaged that victims suffocate. Sometimes the deadliest attacks of all are friendly fire. The immune system’s inflammatory response, which evolved to clear out damaged cells and allow rebuilding to follow, can overshoot the mark, especially when confronted with an especially robust (or wily) invader. When it does, histamines and the other compounds that increase blood flow and ease the passage of fluid through cell membranes cause enough fever and swelling to kill hosts as well as pathogens.
Most victims, nonetheless, survive a first bout with tuberculosis, generally because the colonies of M. tuberculosis lack the time to achieve maximum size before the host’s immune system intervenes. The problem, however, is that the disease doesn’t disappear. It stays latent, waiting for the opportunity to start the cycle of replication. One in ten times the full-blown disease will reappear as secondary tuberculosis, either because of reexposure to the pathogen, poor enough nutrition that the host’s immune system is damaged, or even hormonal changes. The result is that the same host of symptoms attacks a much-weakened host within a few years of the initial infection. Which is what happened to Patricia Thomas.
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