When Alexander Fleming discovered the penicillin mold in 1928, he never considered its possible therapeutic value. NOVA explores the "Fleming myth" and reveals the true story of the scientists who worked behind the scenes to develop the wonder drug of the century.
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00:00From this moldy culture plate came one of the greatest medical discoveries of the 20th
00:15century.
00:16The drug, penicillin, was to save millions of lives.
00:20It was the beginning of a revolution in the treatment of infectious disease.
00:26This development, part of the Allied war effort, is thought by many to be as important in the
00:30outcome of the Second World War as the atomic bomb.
00:35But who should take the credit for penicillin?
00:37It was Fleming's name in Fleming's picture and Fleming's name in headlines that appeared
00:43in the newspapers.
00:44We thought at first this must somehow be a misprint for fluorine, but it certainly was
00:49not.
00:50A long time controversy haunts this tale of a medical miracle.
00:54Tonight, NOVA travels back in time to unravel the mystery behind the rise of a wonder drug.
01:07Major funding for NOVA is provided by this station and other public television stations
01:11nationwide.
01:15Additional funding was provided by the Johnson & Johnson family of companies, supplying health
01:19care products worldwide.
01:24And by Allied Signal, a technology leader in aerospace, electronics, automotive products,
01:29and engineered materials.
01:54Disease, whose guerrilla warfare against the Red Cross flag has hitherto out-generaled
02:03even the greatest commanders, suffers a setback, thanks to the new medical drug, penicillin.
02:17The triumph of penicillin made international news during World War II.
02:22Overnight, legends emerged to explain its strange and marvelous discovery.
02:26This cement stride forward is due to a despised mold, like the common growth on cheese.
02:32Here at St. Mary's Hospital Medical School in Paddington, through this very window 25
02:36years ago, a speck of mold blew in and settled onto Professor Fleming's culture plate.
02:41A mold blowing in through the window makes an enchanting story, but what really happened
02:46is even more dramatic.
02:48Scientific myths abound, but perhaps the greatest surrounds the discoverer himself.
03:03But if it had been left to Alexander Fleming alone, there would have been no drug today.
03:10Many who did the crucial work have been forgotten.
03:14It was Fleming who enjoyed the adulation of a grateful world.
03:20And it was Fleming's story that most of us were taught in school.
03:30The history of penicillin is fraught with conflict and controversy.
03:36Professor Gwynne McFarlane, a scientist and historian, set out to uncover the full story
03:41behind this miracle drug.
03:44In his book, published in 1984, he reassessed Fleming's contribution.
03:49McFarlane started with Fleming's initial discovery.
03:52Fleming kept his original culture plate, and it's now stored at the British Library.
03:57Unfortunately, it is badly decomposed, but a replica shows what caught Fleming's attention
04:03in 1928.
04:06In between a big growth of green mold and yellow colonies of bacteria lay a no-man's
04:10land of dead microbes.
04:13Something coming from the mold had killed them.
04:15That something turned out to be penicillin.
04:21According to McFarlane, this was a classic scientific observation.
04:24But he also points out that Fleming failed to recognize the life-saving potential of
04:28the mold.
04:33A sense of mystery shrouds Fleming's historic discovery.
04:37McFarlane contemplates Fleming's scientific reputation.
04:41Fleming has been widely accepted as a great man and a great scientist by many writers,
04:48popular and a few medical, on a par, as if Fleming was really on a par with Louis Pasteur
04:56or Galileo.
04:58Now I really can't accept this.
05:01Fleming first became a bacteriologist in the same way he would discover penicillin, by
05:06accident.
05:08Fleming had been a rather brilliant student.
05:13And when he qualified, he wanted to become a surgeon.
05:17But in the meantime, he was anxious to get a temporary job at St. Mary's, which would
05:23keep him in the rifle team, because he was a very good shot.
05:28Arrangements were made, and he joined the inoculation department in 1906, where he would
05:32remain for 49 years.
05:35He became absorbed in the study of bacteria.
05:38It was well known that these germs caused disease, but most supposed treatments were
05:42little better than quackery.
05:45Infections were commonplace and often lethal.
05:47They were as feared as cancer and heart disease are today.
05:52I'm old enough to remember hospital wards absolutely full of patients with septic infections,
05:58many of them young adults or children, and many of them who were in hospital for weeks
06:02at a time.
06:06Almost every organ in the body could become a seat of an infection.
06:11And really, there was almost nothing that the doctors could do about it.
06:14For example, I remember very well patients with pneumonia, which was a very common disease
06:20in those days, a very dangerous disease.
06:23Often went on to a complication in which pus formed in the chest.
06:26And then part of a rib would be removed and a tube would be put in, and the patient would
06:32sit in bed, perhaps for five or six weeks with pus draining out of this wound, down
06:38a tube into a large jar under the bed, which might easily contain a pint or two of pus.
06:43And this went on for weeks.
06:44Ironically, while thousands died from pneumonia and TB, an effective treatment was found for
06:58the scourge of high society, syphilis.
07:03After 605 attempts, the German chemist Ehrlich had made an arsenic preparation nicknamed
07:08606, which could cure syphilis.
07:13He sent some to Almroth Wright, the godfather of British microbiology and Fleming's awesome
07:18boss.
07:19But Wright believed in using vaccines for treatment and shunned other drugs.
07:23So he passed Ehrlich's substance on to Fleming.
07:27Fleming was extremely neat and dexterous with his hands and could be guaranteed to give
07:34intravenous injections without the material spilling out into the tissues, which could
07:39be dangerous.
07:40And as he devised an improvement in the method of diagnosing syphilis, he soon had quite
07:45a wide practice.
07:49Fleming's success earned him considerable recognition and the nickname Private 606.
07:55It could have alerted him to the idea of treating infection by injecting chemicals into the
08:00bloodstream.
08:02But under the influence of Almroth Wright, his skepticism of such treatments grew, especially
08:08after their experience in the First World War in France, where they began a study of
08:12war wounds.
08:15Most battle casualties were infected when they arrived in the hospital.
08:21The most common infection was with streptococcus and staphylococcus, but a less common but
08:28very dreaded one was infection by the organism gas gangrene.
08:32This produced a spreading gangrene of muscle which moved with terrifying rapidity, and
08:38unless a surgeon could amputate above this infection, the result was invariably fatal.
08:46Most army surgeons relied on local chemical antiseptics to control the septic infections,
08:55but Wright and Fleming soon found that these antiseptics actually did more harm than good.
09:02The harsh antiseptics destroyed white blood cells and interfered with the natural healing
09:07process. They were nearly useless against infection, so Fleming's doubts about chemical
09:12treatments were confirmed.
09:15He might have gone on to look for new agents which could fight infection without causing
09:19damage, but Fleming took up other interests when he returned to London, as Ronald Hare,
09:24then a researcher at St. Mary's, remembers.
09:27When it came to high class theory and all the other things that make textbooks, he couldn't
09:35be bothered with it at all. He was a damn good technician. If he saw something walking
09:45in on one stick or something, he'd invent something to do with that stick.
09:52People collect stamps, or plants, or observations of birds. Fleming did this with bacteria,
09:58and an example of this, he collected an extraordinary sort of bank of strange bacteria which produced
10:05different colored pigments, and he used to construct pictures, colored pictures, painted
10:12on a culture medium with brushes loaded with these bacteria, and as they developed and
10:17grew, they formed the most beautiful little pictures.
10:22Fleming's more serious investigations did sometimes pay off. Experiments on the fluids
10:27of his nose and eyes led to his first important discovery. Using a squirt of lemon juice,
10:32he collected his own tears. He found that they contained some ingredient which killed
10:37off bacteria in minutes. To continue his experiments, he needed more tears, and so recruited young
10:43lab technicians who lined up to undergo the ordeal by lemon.
10:50Once again, Fleming made news. The humor magazine Punch called his discovery tear antiseptic.
10:59Elmroth Wright christened the new discovery lysozyme. However, lysozyme did not kill disease
11:05causing bacteria. It had no therapeutic value, but it did prepare Fleming for his second
11:10major discovery, penicillin. One day, in the year 1928, he was examining some sepsis germs
11:18grown on jelly before sending them to be destroyed. He noticed that one of the dishes had gone
11:25moldy, and that round the patch of green mold, the sepsis germs were dying. Some powerful
11:31natural antiseptic was obviously exuded from the mold.
11:35Good evening, Sir Alexander. It isn't often that we have the privilege of meeting somebody
11:41who's made such an important discovery as you've made.
11:44Two months before he died, he was interviewed by the BBC. Fleming tried to explain his historic
11:50discovery to the television public.
11:52Well, I got contaminations, and when I looked at them a week afterwards, all sorts of contaminations,
11:59but one of them was a mold.
12:01Now, by contamination with a mold, do you mean the sort of thing that happens to a housewife
12:05if she leaves the top of her jam too long, that sort of thing?
12:09Exactly the same. Exactly the same. Here's a good example provided by the BBC. Here is
12:17a pot of jam, and on the surface here, on top of the paper, there are a number of molds.
12:24Maybe the same mold that I got. Maybe not. I don't know.
12:30Molds are tiny organisms that reproduce by casting off spores into the air. One microscopic
12:35spore on a culture plate or jam jar can grow with incredible rapidity into a large colony.
12:42Molds themselves are common, but very few produce penicillin.
12:48Fleming's turned out to be a particularly rare strain of mold. The discovery was not
12:52as simple as it first appeared. Fleming always believed that the mold had blown in through
12:58the window, but his window was almost impossible to open because of all the supplies he stored
13:03in the sill. It's far more likely that tiny mold spores drifted up the staircase from
13:10the floor below, where exotic strains were being collected for research on allergies.
13:16Even so, it has proved extremely difficult to reproduce the effect Fleming observed because
13:21molds and bacteria each need different temperatures to grow.
13:29Fleming's experiments usually involved growing bacteria on plates and putting them in an
13:33incubator, where they formed colonies. But on this occasion, some plates were left out
13:38in the cold on the bench, and one became contaminated with the mold.
13:44Fleming left to go on vacation, and the English summer weather did the rest. First, an unusual
13:50cold spell allowed the mold to flourish. Then, the temperature went up, and the bacteria
13:55started growing. Beneath the lid of an abandoned laboratory plate, the mold started killing
14:02off the young bacteria. Fleming returned three weeks later. He started sorting through his
14:07old plates. Finding nothing of interest, he dumped them into a tray of disinfectant, ready
14:13to be washed up. Luckily, the important plate was left high and dry above the liquid, only
14:20inches away from destruction. Fleming happened to look through the plates one last time to
14:26show an old friend what he'd been up to. There, among the dirty dishes, Fleming noticed
14:32the extraordinary plate.
14:36The things which had to happen in order to make Fleming's discovery possible form an
14:44almost incredibly improbable series of chance events. I think this really illustrates the
14:51part that luck plays in many scientific discoveries. But this discovery of penicillin by Fleming
14:57must be a supreme example of this. It was a daily event for Fleming to leave his laboratory
15:06down the stairs and come upstairs about 11 o'clock to get a cup of coffee. And then,
15:13on this occasion, he had a culture plate in his hand and proceeded to show it to all
15:19of us. And I think it would be correct to say that nobody took the slightest notice
15:25of Fleming's discovery for a very long while.
15:31Despite the indifference of his colleagues, Fleming embarked on a series of penicillin
15:36experiments. But the substance was unstable and difficult to work with, and he soon moved
15:40on to other projects.
15:43Now the reason why Fleming lost interest in penicillin so early, in a matter of a few
15:51months, in fact, lie in this notebook, which are his original records of experiments. Briefly,
15:59this book shows that he did most of his penicillin experiments in glass containers. And from
16:06these experiments, he concluded that penicillin would very rapidly be destroyed in living
16:13tissues. Now, living tissues and glass are two quite different systems. And, in fact,
16:20Fleming was wrong in his conclusion.
16:23What Fleming didn't realize was that his experiments in glass did not accurately reflect what happens
16:28inside a living human being. His research had convinced him that when penicillin was
16:34mixed with blood, it lost most of its germ-killing power. So he never went on to try penicillin
16:39on an animal injected with a fatal dose of bacteria.
16:45Fleming thought of penicillin as a local antiseptic, rather than a general antibiotic. He concentrated
16:51on its unique use as a laboratory tool for identifying and isolating different microbes.
16:59Fleming sent samples of his mold to other labs so it could be used in research on influenza.
17:07But his published paper did not attract much notice. For ten years, penicillin was relegated
17:14to obscurity.
17:21The story of the re-emergence of penicillin at Oxford has its own share of lucky coincidences.
17:33But it depended on a different approach to science and the determination of an ambitious
17:38researcher who had earned a coveted chair of pathology at the age of 37, Howard Florey.
17:44Florey grew up in Australia.
17:47I remember my father consulting the headmaster and he said, oh no, you can't go into chemistry,
17:53there's no outlet in Australia. And it was then that my thoughts turned to medicine.
18:00As a ship's doctor, he worked his passage to England in 1921. He had won a highly prized
18:05Rhodes Scholarship to Oxford.
18:09One could get away with any sort of gaucheries as far as just one of these rough colonials.
18:16Florey was a rough, tough Australian, completely uncompromising, rather prickly, very energetic
18:23and tense as a coil spring. And he brought to his work this extraordinary dedication,
18:31which was very infectious in such a way that he really could collect a team of people who
18:37became almost as dedicated and enthusiastic as himself.
18:43I had a refugee German chemist named Chain whom I got from Cambridge.
18:52Chain was brilliant by a chemist and I think he knew it. He was extremely excitable and
19:00he used to pace up and down a room while he was talking and hiss loudly before making
19:06some sort of extremely enthusiastic remark.
19:11There's no blueprint to discovery, you see. I mean, this is an individual, it's an art really.
19:18I mean, you can't lay this down. But the general principle is that you go out and you look
19:24for interesting biological odds, interesting new biological phenomena which you hope you
19:30will be able to explain in chemical terms.
19:34He proposed and I agreed to go along with it that we made a thorough investigation of
19:38antibacterial substances.
19:43Chain searched through over 200 scientific papers. Eventually he chanced upon Fleming's
19:48report in a ten-year-old journal.
19:52They already had a sample of Fleming's mould in their culture store. Growing it in small
19:57flasks was simple. But Chain's job would be to get penicillin, the active ingredient,
20:02out of the liquid which the mould produced.
20:07The chemical properties of the substance were most unpromising. It was described as
20:12so unstable that you lost it practically while you looked at it.
20:17Not only was it notoriously elusive, but only one part in two million was penicillin. To
20:23separate it from this vast amount of impurity, they tried using solvents. But when they evaporated
20:29the solvents, they lost most of the penicillin too.
20:32The breakthrough came when Dr. Norman Heatley suggested that changing the solvent's acidity
20:37might free up the penicillin. Chain had been against the idea. He was often a difficult
20:42man to argue with.
20:44For example, he said in one of the early days penicillin was yellow. And I said, well, it
20:51could be, but you have no evidence for this. And his reply was, but Heatley, I am telling
21:01you, it is yellow, yellow, yellow.
21:05Even after Heatley's process, it still contained masses of impurities. Pure penicillin is,
21:10in fact, white.
21:12All gatherings for purposes of entertainment and amusement, whether outdoor or indoor.
21:17In 1939, Britain was on the brink of war.
21:20Large numbers congregating together are prohibited until further notice. Air raid warnings.
21:28Florey made his own film of the lab's preparations for war.
21:33It was hardly a good time to be attempting research. Lack of funds, equipment shortages
21:38and the risk of air raids were a constant threat. Yet Florey was committed to the penicillin
21:43work and focused more and more of his team's efforts to penicillin.
21:47Until you hear the raider's fast signal.
21:54By 1940, Britain was under attack, and the Oxford team was about to make a breakthrough.
22:00On May the 25th, 1940, that was a day I'll never forget. We did an absolutely crucial
22:06experiment to see whether penicillin would prevent the certain death of mice which had
22:13been experimentally infected with a deadly streptococcus, a kind of disease germ. Eight
22:20mice were taken and all were given a certain fatal dose of this organism. Then four of
22:28them were given penicillin.
22:31Heatley kept a diary of the events.
22:35After supper with some friends, I returned to the lab and met the professor to give a
22:39final dose of penicillin to two of the mice. The controls, the ones who hadn't had penicillin,
22:46were looking very sick, but the treated mice seemed very well.
22:50The fate of the mice would determine the future of penicillin. Heatley began his Saturday
22:54night vigil.
22:55I stayed at the lab till 3.45, by which time all four control animals were dead. It really
23:04looks as if penicillin may be of practical importance. I left the labs at 3.45 a.m. on
23:10Sunday, this was, when it was already beginning to grow light.
23:13Before and after, though the shape of the world may alter, in our tunes the laughter
23:21blends the tears.
23:23Went to the lab at 11.45 and found all four treated mice alive and well.
23:29Florey was ecstatic. He immediately phoned Dr. Margaret Jennings, who would later become
23:34his second wife.
23:35When the professor rang me up on that Sunday morning, he expressed his feelings about the
23:41result of this experiment by saying, it looks like a miracle. And as he was usually a person
23:51who was given to understatement, this was very surprising. The expression he used meant
24:00that he was really excited about it.
24:04The next step was to test penicillin in man. But a person is 3,000 times the size of a
24:09mouse. The challenge would be to grow and purify enough penicillin to start human trials.
24:18This meant really scaling up an already very difficult process to a point at which a university
24:26department really had to be turned into a factory. This had to be Florey's decision,
24:33and it was really a very bold one, because this, after all, was a university department
24:38and there was an obligation to teach students and all the rest of it. And to change its
24:44character really so dramatically and extensively might have led Florey into quite considerable
24:52trouble if the venture had not come off.
24:56Molds grow best in shallow containers that have a large surface area. The team's first
25:01problem was to find something to grow the mold in.
25:04What was needed was a layer of medium, not more than half an inch thick, in a vessel
25:11which could be steam sterilized. We used all the laboratory flasks and bottles and containers
25:18that could be used, but they weren't, of course, enough. And we found that you could
25:24grow the stuff in tins, usually enough, and these are some of the equipment we used.
25:31But the best container was the hospital bedpan. The Radcliffe Infirmary let us have 16, which
25:40was all they had.
25:43Heatley then found a pottery firm that could produce an abstract form of the bedpan to
25:47his specifications. On Christmas Day of 1940, he seeded them with penicillin mold. They
25:55were finally able to grow gallons of moldy liquid. Once it was purified, they'd be able
26:00to begin clinical trials.
26:04By January of 1941, they were ready. Dr. Charles Fletcher joined the team. It would be his
26:10task to find a suitable patient. Their first goal was to learn whether or not penicillin
26:15was toxic to humans. Fletcher soon found a terminally ill woman who agreed to be their
26:20test subject. The substance was injected into her bloodstream with no ill effects. Penicillin
26:25was indeed safe for human use. But the trial had been fraught with danger, as Dr. Edward
26:31Abraham knew very well.
26:33It has to be remembered that the penicillin used in the clinical trials was no more than,
26:40in most cases, about 4% pure. And it really was very fortunate indeed that, among this
26:51massive impurity, that there was no substance that was highly toxic.
27:00Finally they were ready to test the drug against infection. Fletcher remembers the case of
27:04a young policeman.
27:06This policeman was particularly badly ill. He'd had a sore in his mouth about a month
27:11previously. Infection had spread over his scalp. He had abscesses there. It had spread
27:16to both his eyes, one of which had had to be removed. He had abscesses that had been
27:21cut open on his arm. He had abscesses in his lung. He was well on his way towards death
27:27from this terrible infection. And we had nothing to lose and everything to gain. So we thought
27:31he'd have a try.
27:33The shortage of penicillin was such that after the first day, I collected all his urine.
27:39His urine had been saved. And I took it in a bottle over to the Dunn Laboratory where
27:45Florian was working, so that the penicillin could be extracted from the urine and used
27:50again on the third day.
27:53And when I got over there, it was absolutely delightful, because Florian was a very taciturn
27:59man, a man of few words. And he would say, well, how's the patient? He was an Australian,
28:05with a bit of an Australian accent. And then Jane, who was an Eastern European, was excited
28:11and said, what's the patient like? Is he doing well? Oh, that's marvellous, isn't it? And
28:14this lovely contrast between these two characters in charge of the work. And every day, I did
28:19that. On the third day, he was having the same penicillin as he had on the first day.
28:23And on the fourth day, he really was dramatically improved. And he was sitting up in bed, and
28:28his temperature had come down.
28:30On the fifth day, the penicillin began to run out, and we couldn't go on. Because, of
28:37course, when they extracted it from the urine, they didn't get it all back, and there just
28:41wasn't enough to go on. And he wasn't cured. He gradually relapsed, and then went on and
28:46eventually died.
28:49With so little penicillin available, they decided the next few cases should be children
28:53who needed much smaller doses. One was a four-year-old boy with an incurable infection behind the
28:59eye called cavernous sinus thrombosis.
29:02It was a condition that I'd always dreaded as a medical student. And I'd never actually
29:06seen a case before. But this pathetic little boy, with his eyes bulging out from the infection
29:11behind them, and absolutely no hope of living. And we started the penicillin infusion. And
29:18after two days, again, he was much better. After four days, he was vastly improved. And
29:23after a week, he was sitting up in bed and playing with his toys. I mean, it was unheard
29:27of. No such infection had ever been cured before.
29:31At last, the story had a sad end. But because the carotid artery at the back of his brain,
29:39it runs through this venous part of the brain, had become damaged by the infection. And one
29:45afternoon, it suddenly broke. And he had a hemorrhage in the brain and died suddenly.
29:51It took almost a year and further clinical trials to support the Oxford team's conviction
29:55that penicillin worked. They successfully treated four other patients, including a baby.
30:00In vessels of all sizes and descriptions, a third of a million men, including the wounded,
30:08were embarked and brought home under the protection of the Royal Navy.
30:13Florey realized that using penicillin to save the lives of wounded soldiers could influence
30:18the outcome of the war. Fearing invasion, he and his staff took measures to protect
30:23the precious substance. There was a risk, of course, that the Germans
30:29might, as Professor Florey said, come roving down Heddington Hill in the Panzers. And so
30:35some of us took a bit of the fungus and smeared it in the linings of our coats in order to
30:42get a few million spores there. And then if anyone had escaped, if the Germans had come
30:47and someone had escaped, one could have started up the culture again.
30:54The clinical trials had exhausted their supplies. The Oxford team needed outside help to grow
30:59and purify more penicillin. But the bombing of London severely limited transportation
31:04of materials to the British drug companies. There were no such problems in America, so
31:09Florey and Heatley headed for New York via Portugal. They were amazed by the freedoms
31:15of wartime Lisbon. There was no blackout. One saw people having, you know, five or six
31:22spoonfuls of sugar in their coffee and music and so on.
31:27They had left behind a disgruntled Chain. Chain was, in fact, furious when he found
31:35that this was happening. But there was a very good reason for Heatley going, because he
31:42was the person who had the clearest experience of the production of penicillin in the laboratory.
31:50On July 1st, 1941, they boarded the Clipper for New York.
31:54The Clipper was amazing. About five compartments, each as big as my room at Oxford, with luxurious
32:01seats, lovely carpets and upholstery. Their precious samples of mold, having crossed
32:07the Atlantic and the Clipper fridge, would now have to brave 90 degrees in New York.
32:15In the summer of 1985, Dr. Heatley returned to retrace a journey that would forge the
32:20course of penicillin development.
32:38With lightweight suits in hand, Heatley and Florey were ready to take on America. Their
32:43mission? To spread the gospel of penicillin. And Florey was up to the challenge.
32:48I think he was a very good salesman. All he wanted to do was to persuade somebody to make
32:54him about a kilogram of the kind of stuff we were using in Oxford and making in Oxford.
33:00He wasn't concerned at all whether this or that firm were going to make it on a big scale.
33:05That was entirely out of his range.
33:09But before they began their work, Florey had an important visit to make, in Connecticut.
33:16His two children, Charles and Paquita, had been evacuated to the United States at the
33:20start of the war. They were staying in New Haven with his old friend and fellow Rhodes
33:27Scholar, Professor John Fulton.
33:30Fulton had told certain people a bit about penicillin and had invited them to meet Florey.
33:37And they were, I think, prepared to believe Florey. They were astonished.
33:45It was an optimistic beginning. Fulton's friends realized the importance of Florey's ambition
33:50and furnished him with valuable contacts.
33:54We were shunted, first of all, to Dr. Tom, who was the sort of eminent father of microbiology.
34:03Intrigued by the therapeutic potential of the penicillin mold, Tom whisked them off
34:07to the gigantic headquarters of the U.S. Department of Agriculture.
34:12Immediately, cables were exchanged with a remote lab in the Midwest.
34:20Within days, they were traveling through the heart of the Corn Belt.
34:27The end of the line was Peoria, Illinois.
34:34Well, this was a little different from when you came on the rocket.
34:44When they arrived in 1941, they were met by Dr. Robert Coghill, who took them back to
34:49his lab. It had been originally set up after the Depression to find ways of using agricultural
34:55waste products. They were already growing molds and bacteria by using techniques similar
35:00to brewing beer. Producing penicillin was just such a fermentation process. It posed
35:05an exciting challenge for Coghill.
35:08We started work on it the next day. That's how important we felt it was. We pulled Dr.
35:15Moyer off the work he was doing at the moment and put him on the penicillin project.
35:21Moyer's great skill was feeding molds. His first step was to check what Heatley used
35:26to grow penicillin.
35:28At Oxford, we had had Brewer's yeast extract, boiled extract. And when Moyer learned of
35:34this, because I was telling him everything that we knew, of course, he said, I'm not
35:39too enthused about yeast extract. We haven't got any. But we'll try some corn steep liquor.
35:48Corn steep is a byproduct of turning corn into starch. After the kernels have been stripped
35:56from the cob, they're soaked in huge vats until the outer husks are softened. The liquor
36:04produced is rich in nutrients and so forms an ideal medium for growing molds. When it
36:10matures, it becomes dark and syrupy.
36:13We have lots of this corn steep liquor around the laboratory. So it was natural that Dr.
36:20Moyer would use it in his early experiments.
36:26At first, nothing did grow. And I remember Moyer saying, I kind of figure we're going
36:33to be doing some plain and fancy cussing around here.
36:37After a couple of weeks of Moyer's cussing, their persistence paid off.
36:40A lot of good work came out of this lab. And this was Dr. Moyer's office.
36:48Remember how he used to hide his notes when we walked in unexpectedly like this?
36:53Yes, I do.
36:54And cover them up so we couldn't see what he was doing.
36:59It took all of Heatley's tact and diplomacy to get along with Moyer.
37:04Moyer was known to be strongly anti-British. And he certainly was. There was a business
37:10of him not telling me what he was doing. I'd been away on a trip. And when I came back,
37:16I said, how are you getting on? What yields are you getting? And he said, oh, we're sometimes
37:20up to 20, 20 units per mil. And I said, well, how'd you do that? That's splendid. And he
37:27said, oh, well, I did some chemicals. And from that time on, I never knew what he was
37:36doing.
37:37The corn steep liquor was surprisingly productive. But later, Moyer published a paper in his
37:42name alone. It meant he could take out patents on the corn steep medium without consulting
37:47Heatley or sharing in the profits. Moyer's actions did not go over very well in England
37:53or with Coghill, his boss.
37:56That was perfectly legal and proper for him to do. But it was not very popular in England
38:05to be paying patent royalties on a British discovery. Later, Dr. Moyer and I had a patent
38:12together on the addition of an important building block to the medium to get more penicillin,
38:20which was extremely successful. And he couldn't do anything without my signature. But I refused
38:28to license that particular patent for use in England or anyplace else. The result was
38:36that Dr. Moyer never spoke to me again after that, and his wife wouldn't even speak to
38:44my wife.
38:47Moyer's corn steep medium was an important step forward, but it was still not enough.
38:53While Heatley persisted in Peoria, Florey went back on the road. His quest for a kilo
38:58of penicillin would take him to any scientist who might have a string to pull and could
39:02get the drug companies interested.
39:32Florey said he sometimes felt like a carpetbagger, but one man would make it all worthwhile.
39:40Richards became a convert and got things moving. As the powerful head of a government
39:47committee on medical research, he contacted four leading drug companies, informing them
39:54that government funds would be available for penicillin research. But their response was
39:59only lukewarm. The drug companies were not interested in him. They were not interested
40:04in him. They were not interested in him. They were not interested in him. They were not
40:11interested in him. They were not interested in him. They were not interested in him. They
40:18were not interested in him. They were not interested in him. They were not interested
40:25in him.
40:26Pearl Harbor is now being attacked. This is an emergency communique from the Hawaiian
40:33Defense Headquarters.
40:34Pearl Harbor changed everything. Now the United States, too, was at war. Casualties would
40:39number in the thousands. From this point on, penicillin production would become a matter
40:43of the greatest national importance. Determined to see penicillin succeed, Richards organized
40:49a meeting that he knew would galvanize the drug companies. Coghill would be his trump
40:53card.
40:54Dr. Richards called on me, and I reported Moyer's work in raising the yield of penicillin
41:02by 34. That was a great surprise to the industrial people, and George Merck immediately got to
41:11his feet and said, if those results can be repeated, we'll get the kilo of penicillin
41:17for Florida.
41:19The other companies soon followed Merck's lead. The new goal was not only one kilo for
41:24Britain, but thousands of kilos for the American troops.
41:28Penicillin has been compared to the Manhattan Project, and I don't believe that anyone's
41:32really decided which was the bigger project. But in a sense, I would make a guess that
41:40maybe more people were involved in the whole penicillin project than were involved in the
41:46development of the atomic bomb.
41:49An historic partnership had been forged, yet the drug companies had to struggle against
41:53their competitive instincts.
41:55Dr. Richards wanted all the drug companies to get together and exchange information,
42:02but because of the antitrust laws in this country, that was a very difficult job to
42:09do. There were a few arrangements made, but I think there was very little interchange
42:21of information. Every company was protecting itself.
42:25And I don't think that was particularly characteristic of any one company. They were in business,
42:29they had to survive, and that was the way it was. But there was a feeling of excitement
42:35throughout everything that was going on, and that did pervade everything we were doing.
42:40There was no question about it.
42:43Norman Heatley was now assigned to Merck and was sworn to secrecy about their progress.
42:48Meanwhile, Florey had returned to Oxford, expecting the quick delivery of his kilo.
42:53But he was in for some disappointment.
42:56Florey did get a parcel from Merck, quite a big one, and he unwrapped it, and inside
43:02was another box, and that was unwrapped with mounting excitement. And inside that was a
43:10third box, and inside that was this tiny sample of penicillin. I wasn't there, but I think
43:18I can imagine some of Florey's remarks.
43:24The American government was strictly controlling the release of the limited supply of penicillin.
43:29Still, there were many requests from hospitals. As Norman Heatley remembers, one of the first
43:34came from Florey's friend in New Haven.
43:37In March 1942, I got a telegram one day from Dr. Fulton saying that the wife of a rather
43:45important person in Yale was extremely sick with streptococcal infection, and could I
43:53ask if there was any penicillin available to treat her.
43:58The important person was Anne Miller, wife of the Yale athletics chairman.
44:04Through Fulton's influence, Merck got permission to send the drug to her doctors.
44:08She became the first American to be successfully treated with penicillin.
44:13I had had whatever scarlet fever serum was available, rattlesnake serum, and of course
44:21the sulfur drugs, none of which touched my infection.
44:26With her temperature peaking at 106 degrees, the question facing her doctors was what dose
44:32to give her.
44:34And I said, well, don't ask me because I'm not clinically qualified. And then he remodeled
44:41the question and said, well, what do you think Professor Florey would say?
44:45And that's, of course, a different letter, you see.
44:48And so I told him I'm quite sure he would say, don't decrease the dose, and so on.
44:54And this went on for a week or two, until Mrs. Miller had quite recovered.
45:01Mrs. Miller's successful recovery became widely known.
45:05Physicians were clamoring for the new drug, but supplies were still low and restricted
45:09to military trials.
45:14The ban on civilian use was lifted for the disastrous Coconut Grove fire in Boston later
45:19in 1942.
45:21Nearly 500 people died.
45:23Hundreds were badly burned.
45:27Penicillin was rushed up from Merck to treat the infected burns.
45:31By now, there could be no doubt that penicillin worked.
45:36And its discoverer, Alexander Fleming, was attaining the status of international hero,
45:41much to the chagrin of those close to the Oxford scientists like MacFarlane.
45:46In the summer of 1942, when we opened our newspapers, to our astonishment, we found
45:51that the credit for these clinical successes and for the development of penicillin in Oxford
45:58was being given to Fleming.
46:00It was Fleming's name in Fleming's picture, and Fleming's name in headlines that appeared
46:05in the newspapers.
46:06We thought at first this must somehow be a misprint for Florey, but it certainly was not.
46:12A letter to the Times from Fleming's boss had started it.
46:19Fleming had asked Florey for some penicillin to treat a dying friend.
46:23The dramatic cure made excellent news.
46:26Fleming gave dozens of interviews.
46:29But Florey, as a matter of professional principle, refused to talk to the press, and the public
46:34remained unaware of his contribution.
46:37Instead, Fleming was being given all the credit.
46:40The newspaper campaign was, in fact, kept going by really quite powerful forces.
46:46There was St. Mary's Hospital, of course, who relied on voluntary contributions.
46:51The second thing was that Almost Wright, who was an influential man, wanted credit for
46:56his department, and Beverbrook, who was a very powerful patron of the medical school
47:02and St. Mary's Hospital and a very generous donor, stated quite categorically that he
47:07felt it his duty to say that the credit did go to Fleming.
47:11And finally, the Ministry of Information undoubtedly wanted publicity for good news.
47:20While Fleming made headlines, several British companies were attempting to mass-produce penicillin.
47:25It may need the product of a hundred flasks to cure a single wounded man.
47:29Pleasant output only meets the priority calls from the fighting fronts.
47:41In May 1943, Florey traveled to North Africa with just enough penicillin to give the drug
47:46its most demanding test, the treatment of war wounds.
47:52His radical suggestions would transform the management of battle casualties.
47:56He took his camera to record the work.
48:04This case is the smallest wound he filmed.
48:07Rather than leave a wound open, the normal practice, he suggested it should be cleaned and sewn up.
48:14Penicillin was then immediately injected through tubes every few hours to prevent infection.
48:26The results were miraculous.
48:30This man would almost certainly have lost his leg had it not been for penicillin.
48:35The British field commanders had been impressed by Florey's treatment of battle casualties
48:40and quickly approved penicillin for military use.
48:44But the problem was still the lack of supplies.
48:48Meanwhile, in the U.S., highly automated bottle plants were now operating.
48:53Even so, it was an inefficient process, falling far short of demand.
48:59They had to find a way to grow penicillin in large tanks, not just on the surfaces of shallow vessels.
49:10It was realized early on that submerged production would be the only way
49:16in which enough penicillin could be produced to meet the demands of the military and civilian populations.
49:22Pfizer did most of the pioneering work on submerged production, but Merck was hot on their heels.
49:28When Dr. Heapy was here at Merck, all penicillin was produced in surface culture,
49:32where the organism grew on the surface of a volume of liquid.
49:36It was a very inefficient way of producing penicillin because it took such a long time.
49:41Therefore, we at Merck decided to develop a submerged process for producing the organism.
49:48We used an old style fermenter, where there is an agitator,
49:54which stirs the organism very thoroughly so it grows from top to bottom.
50:00Also, it is necessary to blow air underneath the fermentation
50:04so that the organism is continually exposed to the air.
50:08This deep culture technique did raise yields,
50:13but persuading the mold to grow in the body of the liquid was still difficult.
50:19A new strain of mold with different growth requirements might solve the problem.
50:25At one point, the War Production Board said that a new culture producing more penicillin
50:31would be worth a million dollars.
50:35Peoria would once again make the breakthrough.
50:39Professor Raper had been searching for a new strain
50:42to replace the original Fleming mold since the summer of 1941.
50:46He enlisted the help of Army Transport Command.
50:50Soil samples were flown in from all over the world.
50:53The molds they contained were analyzed.
50:57The most promising came from Cape Town, Chungking and Bombay,
51:01but the search for an even better strain continued.
51:04We were plating them out and isolating blue-green molds,
51:08checking to see if they belonged to the group that penicillin notatum
51:13chrysogeum belonged to, and then screening them for penicillin production.
51:21We employed a girl to make the rounds of different shops and stores
51:28and bring in moldy materials.
51:30Well, it was in that way that we came across mold on a cantaloupe.
51:38They had searched the whole world,
51:40but the best strain was found on a moldy melon in a local Peoria market.
51:44Having picked this off and having checked it and found it was as good
51:48for submerged and for surface as cultures we then had,
51:52we began to try to improve it.
51:56From this mold, new, even higher-yielding strains were produced.
52:00By causing repeated mutations using X-rays, ultraviolet light and chemicals,
52:05mutant molds were created and the best were selected.
52:09These new strains gave a hundred-fold increase
52:12over the original Oxford yields.
52:16The intensive wartime effort, which had quickly led to the triumphs
52:20of corn-steep mixture, deep culture, and new strains of mold,
52:25finally allowed the mass production of penicillin.
52:30By the middle of 1944, they had made enough penicillin
52:34to treat all 40,000 Allied soldiers wounded during the invasion of Normandy.
52:39D-Day.
53:34What has impressed me most, contemplating the story of the development of penicillin,
53:55is how one needs complementary characters.
53:58Fleming was a brilliant observer,
54:01but really without the character or the drive to work out
54:06and work through the results.
54:10With regard to the Fleming myth, I think I feel a bit despondent
54:15about our ability to change it in any way.
54:19Today, far more people have heard of Fleming than have ever heard of Florey,
54:24and I think this will probably continue.
54:27The 1945 Nobel Prize for Medicine was divided among Fleming, Florey, and Chain.
54:33Finally, Florey and Chain had achieved the scientific credit due them.
54:38But many more still go unrecognized.
54:42And perhaps in looking at how science saves lives,
54:45the credit is not as important as the effort.
54:49The penicillin story is a striking tale of luck, determination, and persistence,
54:54and it is shared by many whose names we will never know.
55:24The Triumphant Development of Penicillin
55:42Next time on NOVA
55:45The triumphant development of penicillin was the first step
55:49towards a golden age of antibiotics.
55:52For nearly a decade, there were dozens of new wonder drugs
55:55effective against a variety of diseases.
55:59But only a few years later, infections were mysteriously on the rise.
56:03The use of these life-saving miracle drugs had itself created a problem, resistance,
56:09which threatened to undo their first bright promise.
56:12The pessimists would say that we may have found all the antibiotics there are to find,
56:18but in 40 years hence, we may look back on the antibiotic era
56:22as just a passing phase in a long history of medicine.
56:25The problem is growing all over the world.
56:29And a recent outbreak at an Australian hospital showed just how vulnerable
56:33even the most modern health care system can be
56:36when superbugs outsmart the chemists.
56:39Join us next week as NOVA explores when wonder drugs don't work.
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57:48♪