Sunday, 12 July 2020 06:18

How a miracle drug changed the fight against infection during World War II

Researcher Andrew Moyer in the U.S. Department of Agriculture's Peoria, Ill., laboratory in 1943. He helped discover the process for mass-producing penicillin. (USDA) Researcher Andrew Moyer in the U.S. Department of Agriculture's Peoria, Ill., laboratory in 1943. He helped discover the process for mass-producing penicillin. (USDA)

In March 1942, 33-year-old Anne Miller lay delirious in New Haven Hospital, deathly ill from septicemia that she developed following a miscarriage a month before. During her stay at the Connecticut hospital, doctors tried every cure imaginable — from sulfa drugs to blood transfusions — as her temperature at times spiked past 106 degrees. 

“She was just incurable,” Eric Lax, author of “The Mold in Dr. Florey’s Coat,” said in a phone interview. “It was like somebody today with covid-19 who is going down the tubes.”

Desperate, her doctors acquired a tablespoon of an experimental drug and gave her an injection. Overnight, her temperature dropped. A day later, she was up and eating again. 

The miracle drug that saved her life? A virtually unknown substance called penicillin.

As researchers around the world chase a vaccine and treatments for the novel coronavirus, the quest echoes the race to mass-produce penicillin in the United States and Britain during World War II.

 

In the days before antibiotics, something as simple as a scratch or even a blister could get infected and lead to death. Before the beginning of the 20th century, the average life expectancy was 47 years, even in the industrialized world, according to the National Institutes of Health. Infectious diseases such as smallpox, cholera, diphtheria and pneumonia cut life short. No treatment existed for them.

Scottish biologist Alexander Fleming had discovered the penicillin mold in London in 1928. Fleming attempted to extract the mold’s active substance that fought bacteria but was unsuccessful, and he gave up experimentation, according to Lax’s book.

Alexander Fleming in his lab in 1942.
(Imperial War Museum)
Alexander Fleming in his lab in 1942. (Imperial War Museum)

As war broke out in Europe in 1939, Australian doctor Howard Florey obtained funding from the Rockefeller Foundation in New York to study Fleming’s discovery further at the University of Oxford. Along with brash German emigre Ernst Chain, and meticulous assistant Norman Heatley, he worked to generate penicillin’s active ingredient.

 

But in the course of their research, Florey confronted an obstacle: Extracting the active ingredient from the mold was terribly difficult. Time after time, the delicate mold would dissolve in the process of extraction, leaving scientists frustrated.

The tablespoon of penicillin that cured Anne Miller represented half the entire amount of the antibiotic available in the United States in 1942. To give her a full treatment, doctors had to collect her urine, extract the remaining penicillin from it at about 70 percent potency, and re-inject it, according to Lax’s book.

Through trial and error, the team had discovered that penicillin was much more effective and safer in fighting bacteria in animals than sulfa drugs, which were the treatment for infections at the time. Discovered by German scientists in the 1930s, sulfa drugs had severe side effects, and researchers were motivated to find an alternative.

 

As they tried to cultivate penicillin, they began a few human tests. In late summer 1940, Albert Alexander, a 43-year-old Oxford police officer, scratched his face while working in his rose garden. The scratch became infected by streptococci and staphylococci and spread to his eyes and scalp, according to “The Mold in Dr. Florey’s Coat.” A few weeks later, he was admitted to an Oxford University hospital and given doses of a sulfa drug for a week. Not only did the drug not cure him but it gave him a terrible rash.

Lax writes that Alexander was in “great pain” and “desperately and pathetically ill” for months as he lay in the hospital with no cure available. The abscesses on his face and arms were “oozing pus everywhere,” Heatley wrote in his diary, Lax notes, and Alexander’s left eye became so infected that in February 1941 it had to be removed.

The bacteria continued eating at him and soon spread to his lungs and shoulders. Desperate, doctors gave him 200 milligrams of penicillin, the largest individual dose ever given at the time, and then three doses of 100 mg every three hours, according to Lax. Within 24 hours, there was a “dramatic improvement,” Heatley wrote.

Alexander’s fever went back to normal and his appetite returned. As with Anne Miller, researchers collected his urine to extract penicillin to re-administer.

Howard Walter Florey in 1945. (Nobel Foundation)
Howard Walter Florey in 1945. (Nobel Foundation)

By the end of February, Alexander’s treatment had used up the nation’s entire supply of penicillin, according to Lax. After 10 days of stability, his condition deteriorated without any more of the drug. A second course would have helped him to fully heal, but there was no more to give him. “Florey and the others watched helplessly as a flood of septicemia swept through him. On March 15, he died,” Lax writes.

 

Heartbroken, Florey, Chain and Heatley continued to hunt for methods to produce more penicillin. Meanwhile, the Battle of Britain raged around them. From summer 1940 into the next year, thousands of civilians were killed each month in bombings on all the major cities of Britain. In fall 1940, 50 million pounds of bombs were dropped on London alone, Lax writes.

Working under tremendous pressure with limited supplies, the Oxford team also realized penicillin’s urgent value in treating wounded soldiers and civilians.

“They knew that of the 10 million soldiers killed in World War I, about half died not from bombs or shrapnel or bullets or gas but rather from untreatable infections from often relatively minor wounds and injuries,” Lax said.

As Europe sank deeper into war, labs around the world got word of the Oxford lab’s penicillin research and began requesting samples. Florey and his team were careful not to send any to German scientists, who could have easily developed them to support the Nazi war effort, according to Lax.

 

The Oxford team was so fearful of the drug falling into Nazi hands that as the Blitz bombings shattered England, the team rubbed their coats with the mold, knowing the spores would live for a long time on fabric, Lax said in a phone interview. That way, if any researchers were captured or had to travel in a hurry, they had it with them and could extract and regrow it.

British pharmaceutical companies were interested in mass-producing penicillin, but they were overburdened by wartime demand for other drugs. Florey and Heatley began looking overseas for help, turning once again to the Rockefeller Foundation in New York. Florey realized that the United States, which had not entered the war yet, had many more pharmaceutical firms than Britain with much more capacity to produce penicillin on a large scale.

Florey struck a deal with his Rockefeller contacts: He and Heatley would show Americans how to produce penicillin molds. In return, Americans would give Florey a kilo of the drug. This would provide the Oxford researchers with enough penicillin to complete human trials for suffering patients like Alexander.

 

The foundation agreed.

In a hazardous trip out of war-torn Europe, Florey and Heatley arrived in New York on July 2, 1941.

Through Rockefeller contacts, Florey had access to major players in the U.S. government to back his project — including the War Production Board and the U.S. Department of Agriculture. A week after arriving in New Haven, Heatley and Florey traveled to the USDA’s Northern Regional Research Laboratory in Peoria, Ill., a farming community about 160 miles southwest of Chicago.

The War Department's “A Race Against Death” poster, which was produced between 1942 and 1945. (Library of Congress)
The War Department's “A Race Against Death” poster, which was produced between 1942 and 1945. (Library of Congress)

Robert Coghill, the head of the fermentation division, agreed to help the Oxford cause if Heatley would stay on in Peoria to get the penicillin mold culture started. Leaving Heatley in Peoria, Florey visited U.S. drug companies in the hope of persuading one or more of them to brew the culture fluid and extract the mold to yield enough for his experiments, according to “The Mold on Dr. Florey’s Coat.”

 

By the fall, Florey had persuaded Charles Pfizer & Co., Eli Lilly & Co., Merck and other drug firms to work on the project, and he returned to Oxford to wait for his kilo of penicillin.

But then war struck the United States: The Japanese attacked U.S. Navy ships anchored in Pearl Harbor on Dec. 7, 1941. The declaration of war on the United States by Germany and Italy changed not only the course of the war but also the course of the development of penicillin, Lax writes. With millions of American lives now at stake, penicillin was no longer just a scientific fascination to U.S. pharmaceutical companies — it was a medical necessity.

Ten days after the Pearl Harbor attack, pharmaceutical companies began escalating penicillin production for the war effort, some experimenting with a process called deep-tank fermentation to extract the drug from the mold. Instead of using bedpans and tins to grow the mold and culling penicillin off the top, as Heatley was forced to do in Oxford, they tried submerging the mold in deep tanks and fermenting it to generate larger quantities of the drug. It was a major breakthrough.

As war escalated throughout 1942, researcher Andrew Moyer led the USDA Peoria lab in finding the most potent penicillin mold that would hold up during fermentation extraction. Each day, he sent assistant Mary Hunt to local markets for decaying fruit or anything with fungal growth to find more-productive strains of the penicillin mold, Lax writes. Earning the nickname “Moldy Mary,” she once found a cantaloupe “with a mold so powerful that in time it became the ancestor of most of the penicillin produced in the world,” according to the American Chemical Society.

“Moldy Mary" Hunt, left, with a co-worker inside Peoria’s USDA Northern Regional Research Laboratory in 1943. (National Center for Agricultural Utilization Research)
“Moldy Mary" Hunt, left, with a co-worker inside Peoria’s USDA Northern Regional Research Laboratory in 1943. (National Center for Agricultural Utilization Research)

Throughout 1943, penicillin production became the War Department’s No. 2 priority after the Manhattan Project’s drive to build a nuclear bomb.

 

In July 1943, the War Production Board made plans for widespread distribution of penicillin stocks to Allied troops fighting in Europe. Then scientists worked round-the-clock to prepare for an ultimate goal: having enough to support the D-Day invasion.

On June 6, 1944, 73,000 U.S. troops landed on the beaches of Normandy, boosted by millions of doses of the miracle drug.

Almost three years to the day that Florey and Heatley arrived in New York, American production of penicillin had risen from 0 to 100 billion units per month using deep-tank fermentation — enough to treat every Allied casualty, Lax writes.

Anne Miller went on to live a long and productive life in Connecticut, dying in 1999 at age 90. The hospital chart that tracked her recovery in that long-ago penicillin experiment is now housed at the Smithsonian Institution.

Florey never did receive his kilo of penicillin. He waited for more than a year for the United States to deliver on its original deal. But with America now waging war on two continents, it wanted every drop of the drug it could produce. - WashingtonPost

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