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Medicine: 20TH Century Seer

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Medical news last week vied with news of the days before invasion. Under the aspect of eternity, the medical news might even be more important than the military. WPB announced that the wonder drug penicillin, for three years practically a monopoly of the Army & Navy, was now being manufactured in such quantity that it can be issued to civilians. Some 1,000 hospitals will be allowed to buy generous monthly quotas for distribution to patients and other hospitals as they see fit.*

For impatient sufferers (many of them dying), the good news came none too soon. Penicillin (sometimes rhymes with villain, sometimes with whistle in) is the best treatment for all staphylococcic infections, all hemolytic streptococcic infections, clostridia infections, pneumococcic infections (of the lining of skull, spinal cord, lung and heart surfaces), pneumococcic pneumonia that sulfa drugs will not cure, all gonococcic infections (including all gonorrhea that sulfa drugs will not cure). Diseases against which penicillin is effective but not fully tested: syphilis, actinomycosis, bacterial endocarditis.

The Scientific Vision. The man who made possible this incalculable alleviation of human suffering is Dr. Alexander Fleming, discoverer of the antibacterial effect of the mold from which penicillin is made. He is a short (5 ft. 7 in.), gentle, retiring Scot with somewhat dreamy blue eyes, fierce white hair and a mulling mind, which, when it moves, moves with the thrust of a cobra. Until time’s solvent has dissolved the human slag, it will be hard to say who the great men of the 20th Century are. But Dr. Alexander Fleming is almost certainly one of them.

For he belongs in the tradition of the scientific seers, which includes Galileo watching the swing of a lamp in the Cathedral of Pisa and deducing from it the law of the pendulum, and Isaac Newton watching the fall of an apple and deducing from it the law of gravity. For thousands of years men looked at the cryptogamic mold called Penicillium notatum, but Dr. Fleming was the first to see its cryptic meaning. His discernment, restoring to science the creative vision which it has sometimes been held to lack, also restored health to millions of men living and unborn.

The story of his discovery is legendary. Back in 1928 Alexander Fleming, M.B., B.S., F.R.C.S.,* taught bacteriology at St. Mary’s Hospital Medical School, University of London. In his small, old-fashioned laboratory, he grew staphylococci in petri plates (flat glass culture dishes). One day he found that mold had spoiled one of his cultures. Staphylococcus grew on only half of the plate. A blue-green mold spotted, but did not cover, the other half.

He noticed that the mold had cleared a wide, bacteria-free area between itself and the staphylococci—perhaps had killed them. He did not destroy the moldy culture.

It was a great moment in the drama of medicine: the moment when Dr. Faustus opens Nostradamus’ secret book, comprehends in a flash the sign of the macrocosm, and is able at last to conjure up the Earth Spirit. But that was not the way Dr. Fleming reported his epochal perception. Said he: “I was sufficiently interested in the antibacterial substance produced by the mold to pursue the subject.”

The Scientific Method. Dr. Fleming stuck a loop of platinum wire into the mold colony, dipped the wire into some mold-growing liquid in a test tube. In less than a week, there was a felt-like growth at the mouth of the tube and a half-inch of cloudy liquid below it. To Dr. Fleming’s amazement, the liquid in which the culture grew, even when diluted 800 times, prevented staphylococci from growing at all: “It was therefore some two or three times as strong in that respect as pure carbolic acid.”

Soon Dr. Fleming had ascertained that: 1) the strange liquid did not harm fresh leucocytes (white blood corpuscles); 2) injections of the liquid did not hurt mice; 3) some bacteria (e.g., whooping cough bacillus) lived in the liquid as cozily as in a baby’s throat. Modest Dr. Fleming saved the moldy plate as a souvenir, still has it.

Next year what Dr. Fleming knew about the mold’s bacteria-baiting by-product appeared in the British Journal of Experimental Pathology. He had found out that the mold was some kind of Penicillium (from the Latin for pencil—the shape of the magnified mold). He named its byproduct penicillin.

The Man. Alexander Fleming was born (1881) in Darvel, in Ayrshire, the son of a farmer. He went to St. Mary’s Hospital Medical School, largely because it won the Rugger cup and had had a championship swimming team the year before. (Dr. Fleming still loves to swim. His other hobby is rifle shooting.) When he graduated in 1908, he took honors in physiology, pharmacology, medicine, pathology, forensic medicine and hygiene, received the University Gold Medal.

He went to work immediately in St. Mary’s pathology laboratory under Sir Almroth Wright, now 83, pioneer in vaccine therapy and grand old man of British Medicine. Sir Almroth whetted young Fleming’s interest in the mysterious destruction of bacteria by white blood corpuscles and the problem of antiseptics. As a captain in the medical corps in France during World War I, Dr. Fleming noticed that the antiseptics then in use (chiefly Carrel-Dakin’s solution) hurt the white blood corpuscles even more than they hurt bacteria. In some cases the antiseptics promoted infection by destroying the body’s own defenses.

After the war, Dr. Fleming went back to the peaceful laboratory and teaching routine which he still follows. He held classes, ate his lunch in St. Mary’s gloomy refectory, where diners are served soup, “cut off the joint and two veg,” rice pudding, prunes, and tea for one shilling sevenpence. Sometimes at the end of the day he went across from the hospital to The Fountains, a potted-palm pub in Praed Street, for a glass of beer before going home to spend the evening with his wife and son (now a medical student at St. Mary’s). Now & again he would write a scientific paper.

Guiding Idea. One idea ran through all his work: he would look for some naturally occurring bacteria-fighter (new term: antibiotic substance) that would not harm animal tissue. The first antibiotic Dr. Fleming found was lysozyme. It occurs in tears and egg white, can dissolve some bacteria, most of them harmless. That was in 1922—six years before the day when he first saw and grasped the meaning of the sterile ring around the penicillium mold.

The Fallow Years. Having made his great discovery, Dr. Fleming went on to other work. He was engaged in many other experiments—no scientist knows just which of his bottles contains the Nobel Prize. In the history of penicillin there ensued eleven years almost as sterile as the area around the penicillium.

The hiatus might not have been so long if during that period Germany’s Gerhard Domagk had not discovered sulfa drugs (TIME, Dec. 28, 1936), which began to save lives so dramatically that the experts dropped everything else to test them out. In 1933, Dr. Fleming himself lent a hand with M & B 693, also known as sulfapyridine. The sulfas almost seemed to be the dream drugs he had looked for. They stopped deadly streptococci, even cured pneumonia. But the more sulfa drugs were used, the clearer it became that they 1) sometimes delayed healing by irritating wound walls, 2) did not work well in serum or pus. When used internally, they can cause severe, sometimes fatal, toxic reactions (TIME, May 8).

The Practical Application. By 1938, when World War II loomed, a good internal and external antiseptic was still to seek. But at Oxford’s Sir William Dunn School of Pathology (53 miles from Dr. Fleming’s laboratory) the man who was to make Dr. Fleming’s discovery save human lives was already at work on the problem. He was Dr. Howard Walter Florey, 45, an Australian-born professor of pathology. He organized a research team to study the practical extraction of capricious penicillin. The team included experts in chemistry, bacteriology, pathology and medicine. Among them : Mrs. Florey, who is also a doctor, and Dr. Ernst Boris Chain, a brilliant half-French, half-Russian enzyme chemist who shares with Dr. Florey the honors for developing penicillin.

Under Dr. Florey’s dynamic super vision, the blue-green penicillium mold began to grow again. The researchers dis covered that the best growing temperature is about 75° F.,that the mold needs plenty of air. At first, Dr. Florey’s researchers got only about a gram of reddish-brown powder (the sodium salt of penicillin —penicillin itself is an unstable acid) from 100 liters of the mold liquid. But at last, after heroic chemical cookery, they accumulated enough penicillin to test the drug on living creatures.

Of Mice and Men. Then eight mice were inoculated with a deadly strain of streptococci. Says Dr. Florey: “We sat up through the night injecting penicillin every three hours into the treated group [four mice]. I must confess that it was one of the more exciting moments when we found in the morning that all the untreated mice were dead and all the penicillin-treated ones alive.” During that historic night, Dr. Fleming’s vision turned into a medical reality.

From mice to men was a long, hazardous step. With practically the whole Sir William Dunn School at work, it took many months before there was enough penicillin to treat a man. Penicillin’s first human guinea pig was a policeman dying of staphylococcus septicemia (blood infection). After five days on penicillin, he “felt much improved.” He felt that way for ten days. Then the bacteria began to multiply again. As there was no more penicillin, he died. Case No. 2 was lost in the same way. The next cases were luckier (TIME, Sept. 15, 1941). At the end of that first series of ten cases, Dr. Florey and his researchers had proved that:

¶ Penicillin is effective against bacteria when injected into muscle or blood stream.

¶ Penicillin by mouth is useless, because it is destroyed by acid stomach juices.

¶ Penicillin works well in the presence of blood serum and pus, is therefore an ideal wound “antiseptic.”

¶ Penicillin disappears from the blood in an hour or so and about half of it is excreted in the urine. Says Dr. Florey: “Like pouring water down a basin with the plug out.”

They also proved that, unlike the sulfa drugs, which cause bacteria to starve to death, penicillin prevents them from dividing and multiplying — they swell up, but for some as yet undiscovered reason, no longer divide. Penicillin does not kill bacteria — it makes them easy for the body defenses to kill. Sometimes bacteria be come “penicillin-fast,” i.e., able to survive in the presence of penicillin. (In the presence of sulfa drugs they may also be come sulfa-fast.)

Dr. Florey and his researchers also discovered that the purer they made penicillin, the paler it was and the less toxic. Since then, no patient has ever had to stop taking penicillin because of toxic reaction.

Vats and Mushroom Cellars. At first, U.S. manufacturers grew the mold in flasks. A few U.S. hospitals made penicil lin by “kitchen culture.” But through the whole winter of 1942, only enough penicil lin was made in the U.S. to treat about 50 patients.

By June 1943, enough was coming through for the National Research Council’s Committee on Chemotherapeutic and Other Agents, headed by Dr. Chester J. Keefer of Boston, to begin doling penicillin out to 22 groups of doctors all over the U.S., who used it on a handful of civilian guinea pigs.

A catastrophe helped put penicillin into large-scale production. Dr. Keefer used penicillin for Boston’s Coconut Grove fire victims (TIME, Aug. 30). U.S. doctors were impressed by the results, demanded penicillin in large quantities. Priority troubles melted away. Last fall, with the help of specially loaned Army expediters, a dozen big drug and chemical manufacturers were running up $20,000,000 worth of penicillin buildings. Some manufacturers never had any pilot plants at all, performed the unheard-of feat of going into mass production right from the laboratory. Big chemical companies which had never fussed with fungus before waited patiently for the blue-green mold. Some distillers, familiar with fermentation, began growing mold in idle vats and financing experimental work in colleges. Mushroom growers around West Grove, Pa. spawned penicillium where mushrooms used to breed.

Doctors and amateurs also began to grow the mold on their own. The usual method was to let penicillium grow on gauze, then use the gauze for a bandage (TIME, Oct. 25).

The Miracle. Last year penicillin patients were still rare enough to be frontpage news. First such case was two-year-old Patricia Malone (see cut) of Jackson Heights, Queens. The New York Journal-American, which begged enough penicillin from Dr. Keefer to save her life from staphylococcic septicemia, last week won the Pulitzer Prize for the story. After that, the whole nation watched one “hopeless” case after another get well.

There were the three doctors in the California mountains last winter who saved a seven-year-old girl when gas gangrene had forced repeated amputations of her left arm up to the shoulder: “As a last resort, penicillin was given after all hope had been abandoned for a recovery, which came like a miracle.” There was a doctor in Sioux Falls, S.D., who was astonished to save a man moribund with osteomyelitis and septicemia after sulfadiazine had failed: “This being the first case in which I have employed penicillin therapy, I feel that the results obtained, to say the least, were miraculous.”

Doctors now know in general which diseases penicillin helps, have worked out a tentative schedule of dosage. Present consensus is that 40,000 to 120,000 units daily, given gradually by vein or intramuscular injection for about a week, should cure the average case with a systemic infection. Treatment for gonorrhea is usually much shorter; treatment for subacute bacterial endocarditis, much longer. For application to wounds, about 50,000 units in salt solution is used, varying with the size of the wound.

Penicillin seems to cure most of the bacterial diseases that the sulfa drugs cure and cures them more quickly, effectively and less dangerously. It also seems to be a quick cure of early syphilis—the first safe and effective drug to kill the spirochete. Sulfa drugs are not effective against syphilis. But penicillin will not entirely supplant sulfa drugs. The sulfa drugs are still necessary for: 1) intestinal infections (penicillin is destroyed in the digestive tract); 2) bacillus coll infections of the urinary tract (penicillin does not attack b. coli); 3) as prophylactics in epidemics of certain diseases like meningitis, pneumonia, gonorrhea (penicillin is excreted too fast to be used for this purpose).

Only a Beginning. Penicillin is already big business, yet Dr. Fleming (who discovered it) and Dr. Florey (who made it tick) have got nothing out of it but praise—doctors generally do not patent drugs. Penicillin will save more lives than war spends, but there has been no military citation. Most tangible recognition so far was the Award of Merit of the American Pharmaceutical Manufacturers’ Association given to Drs. Fleming & Florey last December. Several months ago, a proposal to give Dr. Fleming a grant from the public funds was brought up in Parliament, but nothing came of it.

To Dr. Fleming, whose pioneer mind has reverted to watching and waiting, penicillin is not an end, but a beginning. He foresees that when the chemical structure of penicillin is known, chemists will make many new potent drugs out of it. And his eyes are already fixed on fungoidal infinities. For there are at least 100,000 molds and fungi, any one of which may one day supplant Penicittium notatum, or yield a drug with which to cure the many plagues penicillin leaves untouched. “It would be strange indeed,” says Dr. Fleming, who is hard at work on other antibiotics, “if the first one described remained the best.”

* They will get the drug from 21 manufacturers (two Canadian, the rest U.S.) now or soon to be in production. Manufacturers will make about 100 billion units in May, about 200 billion units by the end of the year. The Army & Navy have plenty of penicillin for current needs (about 12 billion units a month), and a small stockpile against Dday. Normal civilian needs are expected to be 66 billion a month, export needs 15 billion. The 21 factories will have a top capacity of nine pounds (almost 7 billion units) a day, compared with a total production last year of about 15 pounds. Prices now vary from $2.85 to $10 for 100,000 units (last year’s price: $20).

* Bachelor of Medicine, Bachelor of Surgery,Fellow of the Royal College of Surgeons. Lastyear he added F.R.S. (Fellow of the Royal Society), a great honor.

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