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INGENIOUS INVENTORS, INNOVATIVE THINKERS

WAS IT A MIRACLE?

Newborn baby receiving penicillin through IV

Group B streptococcus (GBS) bacterium causes illness in the elderly, pregnant women, and newborn babies. GBS is the most common cause of life-threatening infections in newborns. It can cause sepsis (blood infection), meningitis (infection of the fluid and lining surrounding the brain), and pneumonia. Babies can be saved with penicillin or ampicillin given through a vein.

Photo: zoomstudio@istockphoto.com

THE TRUE STORY
OF PENICILLIN'S
DISCOVERY

The Quest

Dark-haired and good-looking, Dr. Alexander Fleming was working in his lab at St. Mary’s Hospital, which stood near the glittering theatres of London's West End. It was the 1920s, and it is reported that Fleming was wearing a suit and his customary bowtie. The lab was a clutter of petrie dishes, books, papers, and scientific paraphernalia. Fleming had seen men die of staph infections in World War I, and he was hunting for something that would stop the deadly Staphylococcus bacteria.

Born on a farm at Lochfield, in Ayrshire, Fleming had grown up learning to pay attention to details – to the lamb that was missing, the feel of the wind when the weather began to turn, and the colour of storm clouds. Later, when he moved to London to attend the Polytechnic and St. Mary's Medical School, London University, he learned to pay close attention to the details of scientific research. During World War I, his attention was focused on the wounded under bombardment. He was a captain in the Royal Army Medical Corps, and his bravery was mentioned in dispatches.

At St. Mary's Fleming was looking for a sign that something, anything, could take on the deadly staph bacteria. Several years earlier he had discovered Lysozyme, an important bacteriolytic substance which destroys bacteria in the tissues. He had devised sensitivity titration methods to determine the concentrations of substances in human blood and other body fluids. But despite countless experiments growing staphylococcus bacteria in small round petrie dishes filled with nutrient culture, he had found nothing that could overcome staph.

A cascade of unlikely events

One cool day early in September, 1928, Fleming corralled his culture dishes, and put them in a tray. Some of the staph in the dish cultures had started to grow, but Fleming was leaving town for his summer vacation. A colleague dropped by to wish him well.

Fleming left the tray of cultures where he had set it. He didn't clean up. He left things in pretty much the same disheveled state they were always in, and closed the door. He did not close the windows of his lab because they were not open. His work required the air to be still. He took the stairs down, past St. Mary's Morphology lab where researchers were growing and studying molds. Quite invisibly, even before Fleming reached the pavement outside, a cascade of unlikely events had begun.

A month later, after an exhilarating vacation in the country, Fleming returned to London. Heading up to his lab in St. Mary's, and opening the door, he found the place just as disorganised as he had left it. After talking with a colleague he turned at last to tackle his pile of petrie dishes. He planned to consign them to a lethal Lysol bath, but before he did, he gave the staph dishes a cursory review.

Eureka

As Fleming looked down at his dishes, he noticed that one culture appeared distinctly odd. Examining the dish more closely, Fleming saw that staph bacteria had grown around the edge of the plate, but in the center was a yellow-green growth, and around that growth was a clear halo where no bacteria grew. He was immediately flooded with an insight: Something had ‘destroyed’ the bacteria.

Putting the yellow-green growth under a microscope, Fleming identified the freelancer as a rare mold called Penicillium notatum. The vagabond had apparently absconded from the Mycology department, found its way upstairs by an air current or on a coat and made its way into his lab, where it made a felicitous landing in one of his petrie dishes.  

Its timing was serendipitous.  If the Penicillium had landed in a culture plate where bacteria had begun to grow, Fleming would never have seen the halo. This is because Penicillium does not kill bacteria after it has grown. Instead it prevents bacteria from growing by inhibiting cell wall synthesis. The weather had also been helpful.  Penicillium requires cool temperatures to grow, and for a few days London gave the escapee from the Mycology department cool days and nights. Then the weather had warmed, which encouraged the bacteria to grow, though inhibited by the Penicillium. As a result, Fleming could read the writing on his plate.  But just as this was not the beginning of that waterfall of events that led to the "miracle" called penicillin, it was not the end, either.

Pursuit

Fleming pursued the possibilities of his strange little phenomenon, and published a report in the British Journal of Experimental Pathology, but no one seemed interested.  He used Penicillium in his lab, but only as a tool to isolate bacteria. The waters of discovery lay still. A decade passed. 

In 1938, Howard Florey and Ernst Chain were studying antibacterial agents at Oxford. Florey was an Aussie. Chain was a refugee who had fled to Britain to escape the Nazis. They dug up Fleming’s paper, read it, and thought Penicillium seemed worth a clinical trial. There was only one problem: Penicillin was extremely time-consuming and expensive to produce in the quantity required for analysis. Funds were drying up, and research was grinding to a halt over war fears.

Florey, however, was not easily deterred. He turned to America for help, and convinced the Rockefeller Foundation to provide funds. Then he and Chain, with the indispensable help of Norman Heatley, who developed key techniques, began growing mold, and refining it. They were patient men. It took them five months to obtain enough penicillin to treat a few mice. 

An almost unsurmountable obstacle

The penicillin worked beautifully, but their next task was daunting. To treat a human being they would have to grow and refine 3,000 times more penicillin. Determined to succeed, Florey and Chain along with five graduate students and ten assistants worked six days a week for months to produce enough penicillin to treat six patients. Again the penicillin worked brilliantly, but they had to face the facts: Using their methods penicillin would never be grown in quantities large enough to conduct clinical trials. Unless it could be mass-produced, penicillin was useless.

For a second time they turned to America, hoping to convince major pharmaceutical companies to sponsor increased production. Britain was now fighting for its life against the Nazis, and British pharmaceuticals had lost personnel to the war effort. American companies like Merck, Squibb, and Pfizer had the personnel and the money, but were reluctant because what looks like an obvious idea today did not look obvious or promising then.

Penicillin had been given to only a few patients. It was possible it might be found toxic in a larger clinical trial. The Penicillium mold might contaminate other products; the drug's instability and low yields might result in excessive production costs; and if penicillin was ever chemically synthesised, their investment would be lost. Finally, pressured by A. N. Richards, who chaired the Committee on Medical Research of the Office of Scientific and Research Development, the companies agreed. By 1945, the clinical trials had succeeded beyond anyone's wildest dreams, and almost 400 billion units of penicillin were being produced every year.

By then Dorothy Crowfoot Hodgkin, also at Oxford, had used the X-ray diffraction method originally invented by the Braggs to identify penicillin’s molecular structure so synthetic production could begin. The result: Doctors all over the world use penicillin to treat pneumonia, gangrene, syphilis, gonorrhea, and child-killers like GBS, diphtheria and scarlet fever. The lives of millions of people have been and are being saved. Florey, Chain, and Fleming, sporting a bow tie, shared the Nobel Prize for Medicine.

The invisibles

A religious skeptic, Fleming called the discovery of penicillin “a miracle.” Perhaps it was, but his miracle began centuries earlier with real men and women who have remained almost invisible. They include the generous Brits who donated funds in 1845 to establish St. Mary’s as a research hospital, and supported it for the next century along with the Wellcome Institute for the History of Medicine, the Royal Society of Medicine, and the Medical Society of London; the Americans, whose contribution, it is fair to point out, was made possible because Brits had founded the United States in the first place; and last but not least Oxford University, which has encouraged and sustained research since the 13th century. Like a spore, Fleming’s ‘miracle’ had found the perfect culture in which to grow.

And it has kept on growing. In Japan, young scientist Akira Endo read a biography of Fleming, and was so inspired that he researched fungi until he discovered an enzyme that inhibits the formation of cholesterol. It was the first statin, and has saved millions of lives.

 

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Copyright 2006, 2007, 2008 David Abbott & Catherine Glass