Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (10 page)

Fleming had discovered lysozyme, a naturally occurring antiseptic substance present in tears, nasal mucus, and saliva. In order to gather such secretions to extend his investigations, he made colleagues, technicians, and even visitors weep batches of tears by putting drops of lemon juice into their eyes. Peering through his microscope, he marveled that bacteria in the presence of tears became swollen and transparent, then simply disappeared before his eyes. Of equal importance, he found that lysozymes were present in many animal and plant tissues, including blood, milk, and egg whites.

Fleming's accidental illumination revealed that human fluids have some bacteria-fighting properties and that these are parts of the body's defense system essential to life. Unfortunately, lysozyme has relatively little medical use, being most effective against bacteria that do not cause illness. The discovery, however, put Fleming on the lookout for other nontoxic antibacterial substances.

Fleming had made an important step toward discovering how the perfect antiseptic would work. The next month, he reported his findings
as a work in progress before a group of colleagues interested in research. But he was such a bad lecturer—desultory and self-deprecating—that his listeners greeted the presentation with stony silence and asked no questions. All that the audience could gather was that some rare and harmless germ was soluble in tears or saliva. According to Fleming's biographer, “What would later be regarded as an historic event in medical history seemed to have sunk without a ripple.”
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Fleming published five papers on the subject between 1922 and 1927, and these too were met with indifference. He suspected that the “factor” might be an enzyme but did nothing to prove it. Lysozyme came to be regarded as an interesting oddity. Nevertheless, Fleming, not one to depend on outside encouragement, prepared and incubated thousands of slides to observe the effects of bacteria over the next few years, his keen eye alert to the minutest changes.

And then, in the summer of 1928, there ensued an incredible chain of fortunate circumstances that even a scientist might characterize as having been blessed by angels. As is true of events that profoundly changed the lives of many people, Fleming's discovery has become enveloped in myth. The image of the penicillin-bearing mold floating through Fleming's open window from the polluted London air to land on his open culture plate is appealing but apocryphal. Moreover, most people assume that penicillin's potential usefulness was apparent immediately. In fact, it took many years for its miraculous powers to be unveiled.

In his 1970 book
The Birth of Penicillin,
a remarkable feat of medical history detection, Ronald Hare, a bacteriologist and former Fleming colleague, detailed the astonishing sequence of chance events that made the discovery possible. Confusion, ambiguity, and mythology had long clouded the occurrence because of the lack of contemporary accounts and the absence on Fleming's part of notebook entries, journals, and relevant letters. Indeed, the conventional account was not published until 1944, sixteen years after the discovery, once penicillin's usefulness had been demonstrated by Florey and his colleagues at Oxford and the drug had received worldwide interest. The true account is every bit as extraordinary as the myth.

The odds against the discovery were astronomical. Fleming was
working with cultures of
Staphylococcus aureus
from boils, abscesses, and nose, throat, and skin infections. He piled the plates on a bench and looked at them every few days to see what was happening. Each colony, about the size of a letter on this page, was typically golden-yellow. Some bacteria characteristically develop colonies of various bright colors. Fleming set out to investigate whether a change in color of the colonies from different environmental factors might indicate a different virulence.

Fleming had a discerning eye and liked to “play with bacteria.” The artist in him developed a unique palette of colors. For instance,
Staphylococcus aureus
produced golden-yellow colonies, whereas
Serratia
produced a vivid red color,
B. violaceous
violet, and so on. He had collected a whole range of these colorful bacteria and would streak agar plates with them in a carefully planned sequence and placement. In this way, he grew pictures and designs within a four-inch circle—rock gardens ablaze with color, a red, white, and blue Union Jack, a mother feeding a baby—that would appear after incubation, as if by magic, twenty-four hours later.

At the end of July, it was time for Fleming to go on his summer holiday. He left the staphylococcal plates on his bench in a pile of about forty to fifty.
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Upon his return to work on September 3, he started clearing his workbench of old plates, first looking at each one to see whether anything interesting had developed before placing it into a shallow tray of disinfectant to be washed for reuse. (Today's culture plates are plastic and disposable.) This illustrates one of his compelling traits: he always needed, and got, a second chance to notice the interesting fact. When an assistant stopped by, Fleming wanted to show him some of the plates he had put into the tray for disinfection. He picked one Petri dish at random, one which miraculously rested on others and was just clear of the disinfectant that would have destroyed the bacteria cultures on it. It had been contaminated by a mold. This was not unusual, but Fleming was surprised to see that for some distance around the patch of mold, there was a zone cleared of bacteria, presumably due to some substance manufactured by the mold. At one edge was a blob of yellow-green mold, with a feathery raised surface, and on the other side of the dish were colonies of staphylococcus bacteria.
But in a circular zone around the mold, the bacteria had been lysed, dissolved.

Molds are living creatures of the same broad group as fungi. They can be found on jam, bread, wet carpets, damp basement walls. They grow as a tangle of very fine threads that periodically produce fruiting bodies. The fruiting bodies of molds shed millions of microscopic spores, which are the reproductive seeds of the organism. These are carried in the air, and when a spore lands, by chance, on a hospitable medium, it germinates and starts producing a new mold. During its metabolic process of absorbing nutrients, it produces by-products. In the instance that caught Fleming's attention, this by-product was killing bacteria!

Fleming had seen bacteria lyse years earlier when the drop from his nose had fallen on a Petri dish. But he had never seen disease-causing bacteria lyse because they were near a fungal colony. This mold wasn't just preventing bacteria from growing, it was killing all that were present!

Chance had thus alighted on a prepared mind.

Fleming later noted: “But for the previous experience [with lysozyme], I would have thrown the plate away, as many bacteriologists must have done before…. It is also probable that some bacteriologists have noticed similar things… but in the absence of any interest in naturally occurring antibacterial substances, the cultures have simply been discarded.”
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V. D. Allison later paid tribute to Fleming's work patterns: “Early on, Fleming began to tease me about my excessive tidiness in the laboratory. At the end of each day's work, I cleaned my bench, put it in order for the next day and discarded tubes and culture plates for which I had no further use. He for his part kept his cultures… for two or three weeks until his bench was overcrowded with 40 or 50 cultures. He would then discard them, first of all looking at them individually to see whether anything interesting or unusual had developed. I took his teasing in the spirit in which it was given. However, the sequel was to prove how right he was, for if he had been as tidy as he thought I was, he would never have made his two great discoveries.”
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What can be taken as Fleming's untidiness should not be misunderstood.
In truth, it was his way of cultivating the unexpected. He maintained a curiosity about the seemingly trivial or unusual.

Alexander Fleming at his lab bench.

Other elements contributed to the combination of chance circumstances improbable almost beyond belief. The mold that contaminated the culture was a very rare organism,
Penicillium notatum,
ultimately traced to a mycology laboratory on the floor below, where molds from the homes of asthma sufferers were being grown and extracts of them made for desensitization. (
Penicillium
is named from the Latin, meaning “brushlike,” since the fruiting organs have a brushlike form.) Its spore wafted up the stairwell to settle on one of Fleming's dishes at a particularly critical instant, at precisely the time he implanted the agar with staphylococci. If the mold spores had been
deposited later, the flourishing bacterial growth would have prevented multiplication of the penicillium spores.

Penicillium notatum
acts on microbes only while they are young and actively multiplying. A typical colony of staphylococci on a bacteriologist's culture plate consists mainly of microbes that are already dead or well past the stage of growth at which the mold could affect them; the destruction of the relatively few susceptible microbes would not produce any visible change.

In chronicling the story for his book, Hare consulted old meteorological records and found out that an intense heat wave, which had been smothering London and which would have prevented the growth of the penicillium spore on the Petri dish, broke on the day Fleming opened the dish, thereby allowing the penicillium spore to thrive. The following cool spell in London created conditions in which the mold grew first, followed by the bacteria when the weather turned warm again. These were the only conditions, Hare later found, under which the discovery could have been made.

No wonder that Gwyn Macfarlane, Fleming's biographer, saluted this episode as “a series of chance events of almost incredible improbability.” Listing the sequence of events leading to Fleming's discovery, he likened it to drawing the winners of seven consecutive horse races in the right order from a hat containing all the runners.
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Fleming showed the plate to his coworkers, who were unim-pressed. They assumed that the phenomenon was an example of a lysozyme that had been produced by the mold. But Fleming was undaunted. He confirmed that when the bright yellow fluid extracted from the mold was dropped on staphylococcal colonies, after several hours the bacteria died, disappearing before his very eyes. He began to dilute the extract, but even after further and further dilutions up to 1:800, it still retained its killing power, not only against staphylococci but against most other gram-positive bacteria, including streptococcus, pneumococcus, meningococcus, gonococcus, and the diphtheria bacillus. Unfortunately, it had no effect on gram-negative bacteria like those responsible for cholera and bubonic plague.
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The extract, however, was unstable, losing its efficacy over a period of weeks, and he could not isolate and purify the active principle
from the mold filtrate. To his detriment, he was not a chemist and had little background and limited resources for studies on the “mold juice,” as he called it.

Unaccountably, Fleming failed to pursue two critical paths of investigation. Despite the fact that he was a leading physician who was treating hundreds of patients with syphilis, he never tested his mold extract on the syphilis bacterium. Nor did he think to try it on animals infected with streptococci or any other pathogens. If he had, he would have been astonished at its overwhelming effectiveness. He may have been misled by the fact that when he added the penicillin extract to blood in a test tube, it seemed to be inactivated, suggesting that it would be useless in the human body. Disappointed, Fleming concluded that penicillin did not seem clinically promising, only that it might be helpful applied to superficial local infections and that it might be used in the laboratory to isolate certain microbes.

He addressed the Medical Research Council at a meeting chaired by the physiologist Henry Dale, who would go on to become one of the most distinguished British scientists of his time. Again, Fleming's delivery was so mumbling, monotonous, and uninspired that Dale, along with most of the audience, could not fathom the vast potential medical uses of the discovery. Fleming's stoicism was shaken. Looking back nearly twenty-five years later, he described the silence he faced after his presentation as “that frightful moment.”
generally—but uncovered no other with antibacterial activity. Without the continued preservation of Fleming's strain of mold, the discovery would have remained only a scientific anecdote.
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Although he gave subcultures of the precious penicillium mold to several colleagues in other laboratories, he never mentioned penicillin in any of his twenty-seven papers and lectures published between 1930 and 1940, even when his subject was germicides.
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