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Health

The fungus that changed history

Monday, April 27, 1998

By BRIAN KREBS
Special from The Washington Post

In an infirmary in Oxford, England, a middle-age policeman lay mortally wounded. It was 1941, and World War II was raging. German bombs were falling outside, and the man was dying from, of all things, an infection that started with a prick from a rose thorn.

His health deteriorated until physicians started administering small doses of a new, virtually untested drug. The next day, amazingly, his condition began to improve. But then the supply ran out. It was an experimental substance, and no more could be obtained.

The officer relapsed and died within three weeks.

The drug was penicillin, the first antibiotic ever developed, and the man's story reveals the precariousness of life before the advent of the infection-fighting chemicals.

Before antibiotics, diseases such as tuberculosis, scarlet fever, diphtheria, syphilis, and anthrax had no effective treatments and often resulted in death. Today, they usually are curable. The same is true of the many kinds of strep and staph infections that cause afflictions from skin infections to pneumonia.

Antibiotics have even tamed leprosy.

Antibiotic means "against life" -- not a very apt term for medicines that can bring people back from death's door.

Strictly speaking, antibiotics are substances made by microorganisms that stop growth of other microbes or kill them outright. Today, many of these chemicals are synthesized in factories. Most antibiotics used today were found originally in fungi, a form of life that takes nourishment from dead animal or vegetable matter.

The microbes that antibiotics attack are bacteria, one-celled organisms visible only with a microscope.

Antibiotics work in various ways. Penicillin, for example, blocks formation of the bacterium's protective cell wall and prevents its reproduction. Because cells of humans and other animals have no such walls, penicillin has no effect on them. Other drugs, such as erythromycin, interfere with transfer of chemical messages essential to the bacteria's reproduction.

Not all bacteria are pathogenic, or disease-causing. Most are harmless to humans. Many play valuable roles in breaking down organic matter, helping to recycle dead plants and animals.

Antibiotics usually do a fine job of eliminating harmful bacteria. Unfortunately, they can kill helpful ones in the process. Some antibiotics are highly specific, acting only on certain pathogenic bacteria. However, many "broad spectrum" drugs act indiscriminately and kill good bacteria along with the bad.

The first modern antibiotic was penicillin. Although Alexander Fleming discovered the substance in 1929, more than a decade would elapse before it was introduced into medicine. Not until 1940 was it finally purified. Still more years would lapse and lives be lost to infection before penicillin could be produced in large quantity.

The story goes that Fleming, a professor of bacteriology at London University's St. Mary's Hospital, was studying a dangerous bacterial genus called Staphylococcus, which is the cause of staph infections, and was growing it in a gelatinous nutrient material in petri dishes. He had been on vacation and returned to find something odd in a dish accidentally left in the open.

The bacteria had multiplied, forming colonies across the gel. But Fleming noticed a furry, green mold colony at one edge. Around it, the bacterial colonies had died. It looked as if the mold was emitting a substance that killed nearby bacteria.

According to Gwyn MacFarlane, Fleming's biographer, the mold probably came from another lab, perhaps in the form of dry spores that wafted into Fleming's lab and settled on the dish. The suspect mold was Penicillium notatum, from which Fleming later derived the name of his discovery.

Fleming tried to use crude filtrates from the original penicillin mold to treat surface infections in humans, but a colleague, C. G. Paine, achieved success first.

Paine, a former student of Fleming's, was assisted by dermatologist Rupert Hallam and ophthalmologist Albert Nutt in developing several startling cures with the new substance as early as 1930.

Milton Wainwright, a microbiologist at the University of Sheffield in London and author of "Miracle Cure," writes that the first successful use of penicillin came when the three physicians used crude filtrates to treat a miner whose eye had been cut by a flying stone fragment and had become infected. Normally, the victim would have lost the eye, but penicillin cleared the infection, and the man's eyesight was saved.

Paine and Nutt also cured several babies with eye infections, saving each from blindness. Despite these promising results, the doctors abandoned penicillin and moved to other research.

Historians have speculated about why these men turned elsewhere. One stumbling block was the instability of penicillin, which in its original form was difficult to extract from mold colonies and broke down in storage.

Also, there is evidence that Fleming misunderstood how penicillin worked. Apparently, he thought that it boosted the immune system instead of destroying bacteria directly. In any case, a practical method of purifying penicillin continued to evade him.

As a result, penicillin's remarkable potential would go unrevealed for almost 10 more years. The task of purification would be left to a cohort known as the Oxford Group.

In 1933, fearing persecution by the Nazi regime in Germany, Jewish biochemist Ernst Chain fled to Britain and eventually came to work with Howard Florey, a pathologist at Oxford University. Both had been interested in Fleming's earlier discovery of a substance that he had named lysozyme, which lysed, or broke down, bacteria. The substance, abundant in human secretions such as tears, mucus, and sweat, later was found ineffective against seriously harmful bacteria.

By 1938, Chain had read all of the papers he could find on lysozyme and begun focusing on Fleming's 1929 publication on penicillin. Possibly influenced by Paine's successes with the drug, Chain and Florey decided to pick up the traces. By luck, they obtained samples of Fleming's original penicillin mold, still in storage in Florey's department at Oxford.

In May 1940, with the help of bacteriologist Norman Heatley, the Oxford team modified the purification process by stabilizing the pH of penicillin filtrates, a method employed with little notice five years earlier by Lewis B. Holt, a colleague of Fleming's at St. Mary's Hospital.

The new, purified penicillin then was tested successfully on infected mice. Not long after publication of their results in the medical journal The Lancet, the findings came to the attention of Britain's pharmaceutical industry, which had the know-how to scale-up the purification process to make large amounts of penicillin.

However, because of continuous bombing and the threat of a German invasion of Great Britain, hope for large-scale production turned to the United States.

In 1941, Florey and Heatley headed for the United States, carrying freeze-dried samples of the mold. At a U.S. Department of Agriculture research station in Peoria, Ill., they met Charles Thom, a fungus expert who earlier had corrected Fleming's misidentification of the serendipitous mold.

The USDA scientists were experienced at growing large quantities of mold and quickly saw what needed to be done. They employed a process called "deep fermentation," using huge vats of the kind traditionally used to grow the yeast that ferments beer.

It was successful, and scientists eventually increased production tenfold by adding corn-steep liquor, an abundant byproduct of local cornstarch manufacture. The drug then was shipped directly to the battlefront in World War II and used exclusively to treat the wounded.

By 1943, historian Wainwright wrote, penicillin production had become one of the war effort's highest priorities, second only to development of the atomic bomb.

Penicillin would have a dramatic impact. During World War I, infected battle wounds caused about 15 percent of war-related fatalities. Once mass production began in World War II, the infection death rate virtually disappeared. By war's end in 1945, Fleming, Florey, and Chain were awarded the Nobel Prize in medicine for their work.

The emergence of penicillin would spur a search for drugs targeted at specific illnesses. Streptomycin, an antibiotic used to cure tuberculosis, was the next great advance.

Russian-born scientist Selman Waksman had been researching a strain of soil-dwelling microorganisms that are called actinomyces and exude substances that kill certain bacteria. In 1943, Waksman and his team discovered two strains of actinomyces called streptomyces and found that they produced substances remarkably effective in fighting bacteria that cause tuberculosis, whooping cough, typhoid, and dysentery, then major killers.

Research on this new weapon would progress rapidly as a result of experience with penicillin. After streptomycin's discovery in 1943, it took just three years for U.S. drug companies to produce it in bulk. Waksman also won a Nobel Prize.

After streptomycin, scientists in many places began an all-out search for microbially-produced substances that could treat various types of infections. By 1955, of about 3,000 newly discovered chemicals with antibiotic powers, 15 gained wide usage in medical practice. In subsequent decades, both numbers would grow.

Today, about 5,000 potential antibiotics are known, but of them, fewer than 100 have become medically useful drugs.

Copyright © 1998 Bergen Record Corp.

 

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