Allies and Enemies: How the World Depends on Bacteria (13 page)

World War I mimicked all prior wars by costing millions of lives

from infections, many of them minor, received on the battlefield. On

the front, nurses stretched their bleach supply by diluting it until it had no effect against any germ. About half of the war’s 10 million chapter 3 · “humans defeat germs!” (but not for long)

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fatalities came from infections. Duchesne did not get the chance to

alert the world of his anti-infection drug. He caught tuberculosis soon after joining the French army and died at age 37 in 1912.

Another medical student in Germany had already begun his own

hunt for a “magic bullet,” a drug to kill pathogens without harming

the patient. Paul Ehrlich tested 605 different substances in an effort

to find a drug that killed many different types of pathogens but did

not cause harmful side effects in patients. When he tested the arsenic-containing compound, salvarsan, he found it inhibited the Treponema bacteria that cause syphilis. The promising new drug became known as Compound 606. Prior to the discovery of salvarsan as an antibiotic, Western medicine depended on an antibacterial substance that Spanish conquistadors had learned of in South America.

Peru’s Quechua Indians had been using an extract from the cinchona

tree to treat “ague.” In the mid-17th century, Jesuit priests brought

the Peruvian powder to Europe. The substance to become known as

quinine caused little stir in the medical community until it cured England’s Charles II of ague, now known as malaria. The new drugs

energized physicians, biologists, and chemists toward finding other disease-curing compounds hidden in nature.

Chemists soon emulated Ehrlich, whom they had nicknamed

Doctor 606, by testing hundreds of synthetic compounds against bacteria. In the early 1900s, however, chemical companies had little practice in drug research. Their chemical stockpiles were limited to fabric dyes for protecting threads against decomposition by bacteria.

The compounds did not work well in laboratory tests against bacterial

cultures, and in later years most of these substances were shown to

cause cancers. Ehrlich would not realize his dream of finding a single

magic bullet to kill all infectious disease.

Sixteen years after Duchesne’s death, Scottish microbiologist

Alexander “Alec” Fleming prepared for a short September vacation

from his lab at London’s St. Mary’s Hospital. Historians have shaped

the ensuing tale. Fleming had a reputation as a dedicated scientist but terrible housekeeper. His lab overflowed with Petri plates, tubes,

beakers—certainly the makings of a contaminated experiment. While

Fleming was away, rogue mold spores contaminated Petri dishes

filled with
Staphylococcus
bacteria. When Fleming returned, he

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allies and enemies

noticed clear zones in the film of
Staph
cells where a spore had landed, and he concluded that the mold had disintegrated the bacteria. No one is sure where the mold originated. Spores likely drifted from a floor below where mycologist C. J. La Touche’s laboratory was

chock-full of molds. Fleming’s habit of messiness gave the spores plenty of places to land and grow.

More than one stroke of luck converged to propel Alexander

Fleming into history. The early-fall temperatures were warm enough

for bacterial growth but cool enough for mold contaminants such as

Penicillium
;
Staph
cells prefer body temperature while molds prefer room temperature. Fleming had been studying Staph cultures, which are particularly susceptible to the action of Penicillium . Perhaps the most fortuitous break occurred when lab assistant D. Merlin Pryce came by for a casual hello and spotted the Penicillium -inhibited Staph cells among the cultures.

To Alec Fleming’s credit he investigated odd occurrences that

others might dismiss as aberration. He continued studying
Penicillium
. Fleming had assumed that the mold had lysed the bacteria when spores landed on the bacterial film. Only later did microbiologists learn that
Penicillium
targets young, growing bacteria. The mold spores had probably contaminated Fleming’s Staph cultures before he began his vacation.

Fleming published his results in 1929 and gave lectures on the new substance he called penicillin. But because of acute shyness, Fleming reduced the most riveting topics to a monotonous drone, and he failed to inspire his peers. His colleague at St. Mary’s, pathologist Almroth Wright, openly disparaged Fleming’s work. Alec Fleming retreated to his lab and his main interest, a new compound called lysozyme that he had discovered in human tears. (Fleming developed

most of the knowledge biologists have today on lysozyme. This

enzyme serves as a first-line defense against pathogens on the skin or

near the eyes. Fleming’s important discovery would be overshadowed

by his research on penicillin.)

When the British entered World War II, German bacteriologist

Gerhard Domagk had already discovered sulfa drugs. Britain’s doctors saw the advantage these drugs gave the German infantry for

chapter 3 · “humans defeat germs!” (but not for long)

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treating wounds, but their own laboratories offered nothing similar.

In 1938, Oxford University pathologist Howard Florey had teamed with a recent refugee from Germany, Ernst Chain, to find an anti-infection drug for Britain. Chain unearthed Fleming’s 1929 article on the effect of mold on Staph , and the two suspected they had a dia-mond in the rough. Florey and Chain extracted penicillin from the mold, and then began the lengthy, tedious task of purifying and scaling it up to useful amounts. Back in London, Fleming alternated penicillin experiments with lysozyme studies. During the London Blitz he expanded the list of bacteria susceptible to penicillin and designed clever tests to differentiate mildly susceptible bacteria from the highly susceptible.

In late 1940, Florey and Chain published a brief article in a medical journal on a
Penicillium
extract hundreds of times stronger than Domagk’s sulfa drugs in killing gas gangrene Clostridium . Not until August of 1942 did the London Times pick up the story, but it mentioned no scientists by name. Almroth Wright who had so harshly criticized Fleming 13 years earlier pounced on an opportunity. He wrote the
Times
to inform them of penicillin’s discoverer Alexander Fleming, with special credit to St. Mary’s Hospital. The headlines “Professor’s Great Cure Discovery,” “Miracle from Mouldy Cheese,”

and “Scottish Professor’s Discovery” began appearing. St. Mary’s hospital basked in the recognition (and the increased donations) that other London hospitals coveted.

The public had never heard of Florey or Chain, but Fleming and

the scientific community kept abreast of their attempts to scale-up penicillin production. In August, Fleming, who had never developed

the knack for making large quantities of purified penicillin, asked Florey for some of his drug to treat his friend Harry Lambert, suffering with a severe streptococcus infection. Florey rushed to London with his entire stockpile of pure penicillin and showed Fleming how

to inject it. Although Fleming bungled Florey’s instructions, he nonetheless saved Lambert from certain death.

Everyone now wanted to know about the new drug, and Fleming

may have felt obligated to offer uplifting news. He hinted at penicillin’s promise for saving the lives of Britain’s troops. Florey knew

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allies and enemies

better. Britain had reached the limits of its manufacturing capacity. In his view, Fleming and St. Mary’s Hospital reaped publicity and donations based on false hopes. Between air raids, Florey and colleague Norman Heatley had been scrounging jars, bottles, even bedpans to

keep up with the demand for new batches of penicillin. In 1941 both

men obtained coveted tickets for Pan Am’s Dixie Clipper flight across

the Atlantic. On the trip Florey carried a briefcase stuffed with mold

cultures and a handful of vials of pure penicillin with the hope to get help from a large American drug company—they visited Merck,

Pfizer, E. R. Squibb, and Lederle Laboratories—for mass-producing

penicillin. As late as 1942, Britain’s version of mass production involved collecting
Penicillium
extract in bathtubs, and then rigging milking equipment for the purification steps.

Florey’s campaign for penicillin took a lucky turn when he visited

Yale medical researcher John Fulton during his second year in the United States. Fulton told Florey of a local woman, Anne Miller, who

had been dying with a seemingly incurable
Streptococcus
infection.

Fulton had cajoled a few grams of penicillin from Merck in New Jer—

sey, which Florey had visited the previous year. At 3:30 in the afternoon on a cold March day in 1942, Miller had been consigned to death

with a fever over 100 degrees when she received her first dose of penicillin. By 4:00 the next morning her temperature had returned to normal. Miller’s recovery shocked even Fulton. He preserved her hospital charts, which now belong to the Smithsonian Institution. By the close

of the war, American drug companies were producing 30 pounds of

penicillin a year, enough to treat a quarter-million patients for a month.

In his acceptance speech for the 1945 Nobel Prize in medicine

Fleming shared with Florey and Chain, he commented on the future

of antibiotic drugs. Perhaps, Fleming mused, a time would come when anyone with real or perceived illness could get penicillin. “The

ignorant man,” he warned, “may underdose himself and by exposing

his microbes to non-lethal quantities of the drug, make them resistant.” Fleming described a hypothetical scenario of resistant bacteria

infiltrating families, and then entire communities. On that December

day the story of penicillin’s discovery captured the public’s imagination more than the remote oddity of resistant bacteria.

chapter 3 · “humans defeat germs!” (but not for long)

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Mutant wars

Alec Fleming’s fear of antibiotic overuse and misuse soon became reality. Doctors began prescribing antibiotics for minor injuries, headaches, colds, flu, and other ailments. Even perceptive physicians who worried over indiscriminate use of the drugs could be badgered

into prescribing them by patients who felt lousy. The patients did not

know or perhaps did not care that antibiotics had no effect on colds,

the flu, and other viral infections.

In the 1960s, rather than slowing down to do more research on

antibiotics, agriculture stepped up the use to fight imaginary infections and put more weight on livestock or plump poultry before sending them to market. Resistant bacteria began showing up in places in addition to hospitals. A microbiologist taking a sample of bacteria from a person’s digestive tract, skin, or mouth, or from natural waters and soil had a very good chance of finding more than one resistant species.

Antibiotic-resistant bacteria now settle on kitchen counters, gym equipment, and in locker rooms. Franz Reinthaler showed in 2003 that

antibiotic-resistant
E. coli
exists at every step in wastewater treatment,

and most of the strains tested have resistance to more than one antibiotic. The microbial world has become almost saturated in antibiotics

and thus in antibiotic-resistant microbes.

Bacteria excel at adaptability. Bacteria carry genes that confer antibiotic resistance in their large DNA molecule, the chromosome,

and also on small circular strands of DNA called plasmids that stay separate from the chromosome in the cytoplasm. Resistance genes give bacteria the ability to fight antibiotics in five ways: (1) by cleaving antibiotics into pieces, (2) blocking an antibiotic’s penetration into the cell by altering the drug’s normal entry site, (3) pumping the antibiotic out of the cell as soon as it penetrates, (4) repairing any damage the drug does inside the cell, or (5) altering metabolism to lessen the antibiotic’s damaging effects. Put another way, bacteria have at least as many tactics for resisting antibiotics as antibiotics have modes of action.

Penicillin, sulfa drugs, and the other new antibiotics introduced

in the 1940s and 1950s delivered some remarkable cures. Doctors treating very sick patients were probably tempted to try antibiotics on

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