Perhaps the best-known important accidental discovery is Sir Alexander Fleming's discovery of penicillin.  There is more serendipity in this discovery, however, than most people realize, and there are remarkable sequels to Fleming's discovery that ensured its importance, although these sequels are less well known.

Fleming's life is so full of apparently unrelated events, without any one of which it would not have reached the climax it did, that one "feels driven to deny their being due to mere chance," as his friend and colleague, Professor C. A. Pannett, said in his eulogy upon Fleming's death.

Alexander Fleming was bom in rural Ayrshire, Scotland, in 1881.  His father died when he was seven, leaving Alexander's mother to run the farm and raise four children of her own, plus some stepchildren.  Alexander walked to a school a mile away when he was five, and when he was 10, he walked to a school four miles from home.  When 12, the school was 16 miles away, so he boarded at Kilmarnock Academy, but walked a round trip of 12 miles each weekend to and from the train station to his home.  After a year and a half at Kilmarnock, he went to London to join his older brother and resumed his schooling at the Poly, technic.  This study was short-lived, however, because he could not afford it; the 16-year-old Fleming took a job with a shipping company, but still had time to join the London Scottish Volunteers.  With this group he played on a water polo team, and at one time played against a team from St. Mary's Hospital, a part of the University of London.

A few years later he received a small legacy and his brother encouraged him to enter a medical school.  There were 12 of these in London, and Fleming knew nothing about any of them-except the one affiliated with St. Mary's Hospital, which he knew had a water polo team, so there he went.  At the same time Almroth Wright joined the school as a teacher in bacteriology.  Fleming first planned to become a surgeon, but he was offered a position in (then) Sir Almroth Wright's laboratory following his graduation, and he worked in that laboratory the rest of his life, becoming Professor of Bacteriology in 1929.

During World War I Fleming and Wright were sent to France where they worked with wounded soldiers.  Doctors at that time were depending on antiseptics to cure the battle wounds.  But Fleming observed that phenol (or carbolic acid, the most common antiseptic at that time) did more harm than good, in that it killed the leucocytes (white blood cells) faster than it killed the bacteria, and he knew this was bad because the leucocytes are the body's natural defenders against bacteria.

In 1922 Fleming serendipitously discovered an antibiotic that killed bacteria but not white blood cells.  While suffering from a cold, Fleming made a culture from some of his own nasal secretions.  As he examined the culture dish, filled with yellow bacteria, a tear fell from his eye into the dish.  The next day when he examined the culture, he found a clear space where the tear had fallen.  His keen observation and inquisitiveness led him to the correct conclusion: the tear contained a substance that caused rapid destruction (lysis) of the bacteria, but was harmless to human tissue.  The antibiotic enzyme in the tear he named lysozyme.  It turned out to be of little practical importance, because the germs that lysozyme killed were relatively harmless, but this discovery was an essential prelude to that of penicillin, as we shall see.

In the summer of 1928, Fleming was engaged in research on influeriza.  While carrying out some routine laboratory work that involved microscopic examination of cultures of bacteria grown in petri dishes (flat glass dishes provided with covers), Fleming noticed in one dish an unusual clear area.  Examination showed that the clear area surrounded a spot where a bit of mold had fallen into the dish, apparently while the dish was uncovered.  Remembering his experience with lysozyme, Fleming concluded that the mold was producing something that was deadly to the Staphylococcus bacteria in the culture dish.  Fleming reported:

"But for the previous experience [with lysozymel, I would have thrown the plate away, as many bacteriologists must have done before.... It is also probable that some bacteriologists have noticed similar changes to those noticed [by me].... but in the absence of any interest in naturally occurring antibacterial substances, the cultures have simply been discarded.... Instead of casting out the contaminated culture with appropriate language, I made some investigations.

Fleming isolated the mold and identified it as belonging to the genus Penicillium, and he named the antibiotic substance it produced penicillin.  Later he would say, "There are thousands of different moulds and there are thousands of different bacteria, and that chance put the mould in the right spot at the right time was like winning the Irish sweep." The comment about the "thousands of different bacteria" is pertinent, because although penicillin is deadly to many bacteria, including staphylococcus, it has no effect on some other types of bacteria.  Fortunately, the bacteria that penicillin kills are some of those responsible for many common and serious human infections.

The use of molds against infections was not totally novel in 1928.  Louis Pa teur and his co-worker J. F. Joubert showed in 1877 that one microbe could prevent the growth of another.  There are records of molds from bread being used by the Egyptians and the Romans in ancient times, but there are thousands of diferent molds that will grow on bread and only a few of them will produce anything useful against infections Fleming must have known of this, and thus we can understand his amazement.

Fleming went on to show that penicillin was not toxic to animals and was harmless to body cells.

"It was this nontoxicity to leucocytes that convinced me that some day it would come into its own as a therapeutic agent.... The crude penicillin would completely inhibit the growth of staphylococci in a dilution of up to 1 in 1000 when tested in human blood, but it had no more toxic effect on the leucocytes than the original culture medium ... I also injected it into animals and it had apparently no toxicity... A few tentative trials [on hospital patients) gave favourable results but nothing miraculous and I was convinced that ... it would have to be concentrated ... We tried to concen trate penicillin but we discovered ... that penicillin is easily destroyed . . . and our relatively simple procedures were unavailing."

Meanwhile the remarkable success of sulfanilamide had brought chemotherapy into prominence (see the following story on the sulfa drugs).  Attempts by Harold Raistrick, in collaboration with Fleming, to isolate and concentrate penicillin were unsuccessful and nothing more was done about penicillin for several years.  In the late thirties, Howard W Florey, a professor of pathology at Oxford University, began a research collaboration with Ernst Boris Chain, a Jewish refugee biochemist from Hitler's Germany who had been brought to Oxford by Florey.  They initiated research on lysozyme, the antibacterial enzyme discovered by Fleming, and other natural antibacterial substances.  Their work quickly centered on penicillin as the most promising of these agents.

Using sophisticated chemical techniques of isolation and concentration that were available at Oxford and were familiar to Florey and Chain, but not to Fleming at St. Mary's, the Oxford team succeeded in concentrating and purifying penicillin to such an extent that they could demonstrate its curative properties, first on experimental infections in mice, and then on human patients suffering from staphylococcal and other serious infections. (The first penicillin used on humans was grown in hospital bed pans; some clinical tests were terminated prematurely owing to the scarcity of the drug, even though it was recovered from the urine of patients and reused.)

Because of the urgency of potential use against disease and the wounds of military personnel in World War 11, production on a large scale became a prime concern, both in Britain and in the United States.  Florey came to the United States to describe the methods of extraction and production used in Britain, and chemists on both sides of the Atlantic worked feverishly to determine the chemical structure of penicillin and to produce it by synthesis or by fermentation.  This sensitive and complicated molecule was first synthesized long after the war, but progress in developing production by fermentation during the war was phenomenally rapid.

Serendipity entered into this phase of the production of penicillin, as well as in its discovery.  When Florey came to the United States to consult on means of producing penicillin on a large scale, he visited the Northern Regional Research Laboratory of the U.S. Department of Agriculture in Peoria, Illinois.  This laboratory had for some time been seeking an industrial use for surplus cereal crops and the solution to the related problem of disposing of a viscous extract that was a byproduct of the corn milling process.  When this extract was incorporated into the culture medium for penicillin, it unexpectedly increased the yield of the desired mold by a factor of 10.

A second contribution by the Peoria laboratory came from the development of an improved strain of penicillin-producing mold.  Hundreds of molds from all over the world were collected and brought to Peoria for testing.  Unbelievably, the winning contribution was made by a local woman named Mary Hunt, dubbed "Moldy Mary" because of her enthusiasm for searching for new mold sources.   She brought a cantaloupe from a Peoria fruit market that had a mold with a "pretty, golden look." This new strain of mold doubled the yield of penicillin, so that the combination of the two discoveries at Peoria increased the yield of penicillin by 20-fold.  Who could have predicted that Peoria would contribute so significantly to the production of the miracle drug discovered accidentally in London?

Not only were thousands of lives saved by penicillin during the war, but also research was stimulated for the discovery of other antibiotics, including a family of compounds related chemically to penicillin known as cephalosporins.  Some of these newer antibiotics are effective against bacteria that are resistant to penicillin.

Fleming, Florey, and Chain shared the Nobel Prize in Physiology or Medicine in 1945.  All three were subsequently knighted for their work, which had resulted in the relief of much suffering and the saving of uncounted lives.

Sir Alexander Fleming was aware of his encounters with serendipity.  He once said, "The story of penicillin has a certain romance in it and helps to illustrate the amount of chance, or fortune, of fate, or destiny, call it what you will, in anybody's career." I hasten to add that if it had not been for Fleming's intelligence, or sagacity-to use the term that was an essential component of Walpole's definition of serendipity-the accidents that happened to Fleming would have come to nothing.