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Howard Florey

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Howard Florey - Penicillin:
This was a truly impossible task because penicillin is prescribed to so many people in so many forms for so many things, some life-threatening, others not. Hailed as a miracle drug when introduced during WWII, penicillin continues to fight infection around the world, and the number of lives saved offered here probably just scratches the surface. One Swedish source cited 200 million lives saved but without explication. Although widely used in the developing world, there is virtually no accessible data. This statistic includes penicillin as used for treating sepsis, bacterial meningitis, syphilis, and pneumonia, but does not include treatments for other maladies, nor the use of penicillin derivatives.
--Amy R. Pearce, PhD

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Howard Florey

(September 24, 1898 - February 21, 1968)
Born in South Australia
Year of Discovery: 1940

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The Real Brain Behind the Discovery of Penicillin!

Howard Walter Florey was a medical research scientist who created and oversaw the creation of the first antibiotic - penicillin. Before that time, doctors tried medicines based on mercury or arsenic, using minute quantities so they wouldn’t be toxic They didn’t work very well – the low quantity used to offset toxicity also offset their effectiveness.  Children were used to losing playmates to diphtheria, meningitis, rheumatic fever, or scarlet fever. Even in the U.S., many women giving birth developed “childbed fever” – a fatal infection developed by women soon after delivering a baby. Adults commonly died of syphilis, sepsis, or pneumonia. These dangers disappeared quite suddenly in 1942 with the advent of penicillin. Its use revolutionized medicine and can be viewed as the start of modern medicine.

Florey headed a team of British scientists that were on a journey to find a substance that could destroy bacteria with little or no side effects to the patient. They understood substances with this property were needed thanks to Louis Pasteur, who proved that invisible organisms called bacteria all around us, are the cause of many diseases. Amongst the substances they chose to study was a mold called penicillium, which had been found to have antibacterial properties – also known as an antibiotic property.

In England, Florey created and led the team that discovered penicillin, which was the chemical the mold produced that had such potent antibiotic properties. He banded together a group of scientists that were almost as diverse in their field as their personalities. Among them was Ernst Chain, a chemist, and Norman Heatley, a biologist and biochemist. The team worked towards the extraction and purification of the antibiotic, overcoming numerous excruciating scientific difficulties, all while the threat of a German invasion during World War II threatened to stop their research. Later, this monumental achievement was honored when Howard Florey, Ernst Chain, and Alexander Fleming received the Nobel Prize for Physiology and Medicine for their contributions in bringing penicillin to the world.

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by Adam Allie


Bookcoverjacket


Table of Contents

Introduction
Key Insight
Key Experiment or Research
Key Contributors
Quotes by Howard Florey
Quotes About Florey
Anecdotes
Excerpt from Scientists Greater than Einstein
Similar Scientists
Fun Trivia
The Science Behind the Discovery
Personal Information
Science Discovery Timeline
Recommended Books About the Science
Books by Howard Florey
Books About Florey
Awards
Major Academic Papers
Curriculum Vitae
Links to Science and Related Information on the Subject
Sources









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Florey Quotes
Florey's Humor
The Beginning of Modern Medicine
Florey's Infectious Vitality
Florey's Money Worries
1950s Children's Rhyme
Florey's Trickery




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Key Insight

Florey had a strong belief that the study of disease would "not go very well without a very big injection of chemistry into it," and that in order to truly understand medicine, scientists needed to find the specific active chemicals within the mostly compound substances that nature provided. He broke down the problem of penicillin into five puzzles: What is the best way to grow the most potent mold rapidly? Which bacteria does penicillin kill? How does it kill? What are the side effects on human cells? And, what is its chemical structure? He found scientists with specialties to help achieve each of these objectives and used his organizational talent to bring all their individual disciplines and personalities into a coherent working group. In the end, his insight into what it took to investigate and develop a drug was correct, proven through his methodical approach.

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Key Experiments or Research

 



Key Contributors

 

The Team
Explore other scientists who furthered this lifesaving advance.

Lifesavers: Penicillin

Alexander Fleming
Discovered penicillin, after returning from vacation and finding an unusual mold growing in his culture plates.
Ernst Chain
He refined penicillin, allowing for mass production of the world's first antibiotic.
Norman Heatley
He engineered the methods to grow sufficient quantities of penicillin for testing and refinement.



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Quotes by Howard Florey

"One becomes rather lost in a maze at the thought of stopping the appalling thing of seeing young people maimed and wiped out while one can do nothing."

"There is no question, we will have to go for penicillin. My worry is that I've got the bacteriologists and biologists, and I've got my team together. If the money doesn't come along, I might not be able to hold them together and it would all be finished."

"It looks like a miracle."
-Upon seeing that mice infected with virulent streptococci survived when treated with penicillin.

"The penicillin work is moving along and we now have a fairly substantial plant for making it here. It is most tantalizing really, as there is, for me, no doubt that we have a most potent weapon against all common sepsis. My wife is doing the clinical work and is getting astonishing results - almost miraculous some of them... I am afraid the synthesis of the substance is rather distant, but if say, the price of two bombers and some energy was sunk into the project we could really get enough to do a considerable amount."
-To his former professor, Sherrington

"This is the sort of thing that only happens to you once in a life."
-When asked how it felt developing penicillin

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Quotes about Florey and Penicillin

"I have never met an educated man whose conversation stayed so close to the ground. It was as if he deliberately shunned subtle or polished speech."
-Professor Henry Harris, about Florey

"Nevertheless, it was Florey's personality that captured so many able young research workers, who had been initially attracted by his scientific reputation. What they found in him was an infectious vitality: great physical energy combined with an independence of mind that seemed to open mental windows and let the fresh air of realism clear away stuffy academic pomposities."
-Gwyn Macfarlane, associate and biographer

"We could hardly believe our eyes on seeing that bacteria could be killed off without at the same time killing the patient. It was not just amazement, it was a revolution."
-Dr Lewis Thomas

"Prior to penicillin and medical research, death was an everyday occurrence. It was intimate."
-Katherine Dunn

"It is difficult to convey the excitement of actually witnessing the amazing power of penicillin over infections for which there had previously been no effective treatment,"
-Dr. Charles Fletcher

"Soon young ladies will be able to buy their lipsticks impregnated with penicillin. They will still have their lips made beautiful and inviting, but the danger of infection that every kiss potentially can transmit will be removed. Penicillin will be like a guardian angel ready to halt any intruder that is unwelcome. Facial creams, mascaras and of course, all toothpaste will be impregnated with penicillin too, thus preserving skin and teeth healthy and unblemished."
-George Bankoff

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Anecdotes

Make Penicillin Not War

On September 1st, 1939, the Nazis invaded Poland, and two days later Britain, and their allies declared war against Germany. Heatley had planned on moving to Europe, but suddenly that no longer seemed wise. Florey seized the opportunity to ask Heatley to rejoin the team to work on penicillin, but Heatley flatly refused, knowing how unhappy he would be working under Chain. By now, however, Florey had become an expert at managing discordant personalities. He quickly countered that Heatley could report to him instead of Chain. Heatley accepted and went to work, and Florey never bothered to divulge the new setup to Chain. Because Florey was present each day, ready to discuss the research, Chain failed to notice that Heatley was no longer his assistant. It wasn't until thirty years later that Chain learned the truth, admitting, "I understand now many actions of Heatley which were inexplicable to me at the time."

Ignorance Abounds

Before his discovery, Florey practiced medicine and found it dramatically different from his studies. Since doctors had few cures, they concealed their ignorance by using big words and pompous phrases. He wrote, "I'm now ‘Doctor' to the patients and I have to cover my ignorance by waving my arms and looking grave."

Make a Mess Please

After being hired at Sheffield University, his electors instructed him, "We don't care what you do as long as you make a mess in this laboratory; it's been too clean for a number of years." Florey, who liked to perform one experiment every day - including Sundays - enthusiastically complied. Florey usually was running five or six lines of experiments, each with different collaborators, and he published academic papers widely.

Highway Robbery

Florey found the biggest problem was the tight budget constraints on his research, caused by the slowly fading Depression. He cut expenses to the bone, getting rid of the barrels of beer at meetings and even going so far as to ban use of the lift to save ₤25 a year. Over the next five years, Florey would hit up almost all of the organizations in England that granted research funds for money until he was sick of it, writing Mellanby: "The financial difficulties of trying to keep work going here are more than I am prepared to go on shouldering as it seems to me that I have acquired a reputation of being some sort of academic highway robber because I have to make such frequent applications for grants from all sorts of places.... You may gather that I am fed up." The root of the frustration was evident when he told his friend R. Douglas Wright, "My worry is that... I've got my team together. If the money doesn't come along, I might not be able to hold them together and it would all be finished."

The Mucus Man

One day, in the 1950s, a young student saw an older man in the hallway at Oxford and asked a friend who he was. His friend replied, "At breakfast a couple of days ago I saw that chap sitting on his own. He let me join him. I asked him what he was doing. He said he was working on mucus."

"My God," the student replied. "How sad. Here's a man probably in his sixties, probably at the end of his career, studying mucus."

The man was Howard Florey, discoverer of the drug penicillin.

Excerpt from Scientists Greater Than Einstein: The Biggest Life Savers of the Twentieth Century

Finally, Florey and his team were ready to end their preliminary tests and perform a test on a living animal. At 11 AM, on Saturday, May 25, 1940, Florey and Kent injected eight white mice with a dose of virulent streptococci known to kill. At noon, they gave two mice an injection of 5 ml of penicillin, and two others 10 ml. The other four were controls, so they received none. That afternoon, Florey, Heatley, and Kent watched the mice. Around six, Florey sent Kent home, then gave the first two mice another next dose. By 6:30, mice one, two and three looked fine. Mouse four looked so-so. The controls looked sick. The scientists went home to eat. At 10PM, Florey returned to give mice one and two another injection. The mice acted about the same as at six, so he went home. Heatley returned around eleven and began marking down the times of death of the four control mice. The last one died at 3:28 AM. The next day Florey, Heatley and Chain met to go over the results. The four mice that had received penicillin were still alive. Florey, ever known for his understated manner, called Margaret Jennings. "It looks like a miracle," he told her.

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Excerpt from Scientists Greater Than Einstein: The Biggest Life Savers of the Twentieth Century

Buy a copy in the online store

The Miracle

Finally Florey and his team were ready to end their preliminary tests and perform a test on a living animal. At 11 AM on Saturday May 25, 1940, Florey and Kent injected eight white mice with a dose of virulent streptococci known to kill. At noon they gave two mice an injection of 5 ml of penicillin, and two others 10 ml. The other four were controls, so they received none. That afternoon, Florey, Heatley, and Kent watched the mice. Around six Florey sent Kent home, then gave the first two mice another dose. By 6:30 mice one, two and three looked fine. Mouse four looked so-so. The controls looked sick. The scientists went home to eat. At 10PM Florey returned to give mice one and two another injection. The mice acted about the same as at six, so he went home. Heatley returned around eleven and began marking down the times of death of the four control mice. The last one died at 3:28 AM. The next day Florey, Heatley and Chain met to go over the results. The four mice that had received penicillin were still alive. Florey, ever known for his understated manner, called Margaret Jennings. "It looks like a miracle," he told her.
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Fun Trivia

In the eighteen months the team had been producing penicillin, they had produced a total of 4 million Florey units for all of their experiments and human trials. The ideal dose for a single patient, it would later be learned, turns out to be 4 million units each day.

Scientists at the University of Georgia have estimated that the number of bacteria on the planet approaches five million trillion trillion - that's a five with 30 zeroes after it.

There are about ten times as many bacterial cells as there are human cells in our bodies.

Each square centimeter of your skin carries about 100,000 bacteria.

Most of us carry around over 500 species that add about three pounds to our body weight.

Most bacteria are actually harmless.

Hospitals were very different in 1942 without antibiotics. Each had a septic ward, in which about half the people who entered the wards exited on gurneys to the morgue.
In case of a German invasion during World War II, Florey, Heatley, and some of the other scientists smeared spores of the penicillin mold into their clothes, where it could remain hidden, dormant for years.

Fifty years after the advent of penicillin, amoxicillin was still the most prescribed drug in the United States, constituting 3.8 percent of all the prescriptions in the country in 1994.

Bacteria (and many viruses) can reproduce as fast as every 20 minutes.

Two million people in the U.S. get infected in hospitals each year, according to the National Institutes of Health. Seventy percent of the bacteria that cause these infections are resistant to at least one antibiotic.

Houdini died in 1926 of an appendicitis infection that penicillin likely would have cured.

It is a myth that penicillin was discovered by noticing it growing on a slice of bread.

The first penicillin extraction plant was made from junk. Norman Heatley made it using an old bath tub, milk cans and assorted pieces of discarded equipment.

Within 10 years, penicillin was such a part of everyday life it became the subject of a new version of a popular children's rhyme:

Mother, mother I am ill,
Send for the doctor from over the hill,
In comes the doctor,
In comes the nurse,
In comes the lady with the alligator purse.
Penicillin says the doctor,
Penicillin says the nurse,
Penicillin says the lady with the alligator purse.

Now over 50 million kilograms of penicillin are produced each year worldwide (that's 110 million pounds, or 55,000 tons).

Before penicillin, about half of the people who were hospitalized for a major bacterial infection died.

With the use of penicillin, the mortality of young people with bacterial pneumonia fell from 66% to 6%.

To this day, all it takes to cure a person of syphilis is one shot of penicillin (it takes three shots for people infected for more than a year).

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The Science Behind the Discovery of Penicillin

Growing Penicillin, the Mold

Norman Heatley's first task was to ramp up the growing of penicillin, the mold. Only if they could grow a lot, could they get enough of the extract it produced that had antibiotic properties to test. He proved to absolutely be the right man for the job. Gwyn Macfarlane, a colleague and later a writer about the discovery, said of him, "He was a most versatile, ingenious and skilled laboratory engineer on any scale, large or minute. To his training in biology and biochemistry he could add the technical skills of optics, glass and metal working, plumbing, carpentry, and as much electrical work as was needed...Above all, he could improvise - making use of the most unlikely bits of laboratory or household equipment to do a job with the least possible waste of time."

The mold seemed to grow best on the surface of a solution no more than 1.5 centimeters deep, so Heatley grew it in anything shallow he could find, including trays, dishes, flat bottles turned on their side, and sixteen hospital bedpans borrowed from the infirmary. He added nitrates, sodium, salts, sugars, phosphate, glycerol, oxygen and carbon dioxide - anything he could think of. None of these helped the mold grow. Around Christmas, 1939, a visiting friend of Florey's suggested adding brewer's yeast, which cut the fermentation time in half, although it did not increase the yield. Over the next year, Heatley made improvement after improvement to the lab's brewing methods. He found that it was best to begin by sterilizing the containers in an autoclave - a pressurized cooker. Then he would incubate the penicillin mold on a layer of Czapek-Dox liquid, a nutrient solution used to grow fungi. In a few days, a yellowish gelatinous film formed on top of the liquid, which became covered by green spores. Below it, the liquid turned yellow from dissolved drops of penicillin-containing broth, which would increase in quantity for ten days. Heatley found that if he drew off the nutrient liquid and replaced it, the mold would continue to produce more penicillin. He could usually do this up to twelve times before the mold stopped dropping penicillin into the liquid below.

Next, he needed a reliable test that could compare its strength when he harvested it at different stages of growth. He began his assays using a technique of Florey's that involved a Petri dish with holes cut in it. He placed wax-like agar in the dish and colonized it with staph bacteria. Penicillin derived from varying stages of growth was dropped into the holes to see which had the greatest effect on the bacteria. This wasn't precise enough, so Heatley designed a technique that replaced the holes with porcelain tubes. This allowed for identical amounts of penicillin to be uniformly dropped into the bacterial colonies. After placing the penicillin into the tubes and allowing time to pass, he could measure the size of the growth-free halo around each cylinder, which indicated how much bacteria had been killed. Using this technique, Heatley optimized growing penicillin to produce the most potent extract possible.

Because World War II so disrupted drug company research in England, Florey had to turn to America to produce enough penicillin to be used as a human drug. He took Heatley with him to America, where he stayed for a year, working at the Bureau of Agricultural Chemistry and Engineering, a federal agency of the Department of Agriculture, in Peoria, Illinois, showing them what he knew about growing penicillin.

The scientists in Peoria had quick success in using corn steep liquor and sugar milk instead of yeast in the fermentation process. Corn wasn't grown commercially in England, but in Peoria its derivative was the first choice for all fermentations, for it was rich in nitrogen, which promotes growth of molds and other forms of life. The researchers realized that penicillin was produced by many different strains of the penicillium mold, so they began looking for ones that might produce a more potent extract. They had samples parceled to them from all over the world, but also sent a lab worker, Mary Hunt, to local supermarkets to bring back moldy fruit and vegetables, which they would then culture. One day "Moldy Mary," as she was known, brought back a cantaloupe infested with mold so powerful that it became the source of most of the world's penicillin for years. Now there were two penicillins, with the much more potent American version, Penicillin G, differing molecularly from the British Penicillin F.

Purifying Penicillin

Chain tested penicillin's stability in solutions at varying pH levels and found that it was stable only at the edges of acidity and alkalinity, from pH5 to pH8 (pure water is neutral pH7, lower pHs are acidic, and higher are alkaline). Since he knew his penicillin broths contained many impurities, he tried conventional methods - extracting the active substance by dissolving it in various solvents. The idea was to find a solvent in which penicillin was more soluble than it was in the moldy broth. Chain found that the weakly acidic penicillin could be extracted into ether, leaving the neutral impurities behind in the water layer. But when Chain tried to remove the penicillin from the ether, it seemed to vanish.

Heatley then made a breakthrough. He speculated that reversing Chain's steps might work. If the slightly acidic penicillin would dissolve in ether, perhaps a slightly alkaline solvent would pull it back out of the ether. Heatley filtered the mold juice to remove the large particles of mold, then mixed it with ether as Chain had done, and let the ether, which now contained penicillin, rise above the remnant juice. He then mixed the lighter ether and penicillin mixture with an alkaline solution of buffer salts dissolved in water. He tested it and the water layer now held the penicillin. What's more, it remained in the water even eleven days later at room temperature. Heatley had found a way to stabilize penicillin. This allowed the researchers to create a "standard solution" and define a "unit" - now sometimes called the "Florey unit" or "Oxford unit" of penicillin.

Over time Heatley mechanized and greatly improved the extraction of penicillin into ether, building an apparatus to separate penicillin from its broth at a much faster rate. Once the penicillin-containing solution deposited by the mold was filtered to remove bits of mold and other contaminants, the liquid was jet-sprayed down a long tube while a stream of ether (later replaced by amyl acetate) flowed upwards past it in the same tube, so that the two liquids had a large surface area of contact. The penicillin dissolved in ether and rose to the top, while much of the rest of the original solution sank and was drawn off. But the problem of how to remove the penicillin from the ether remained.

Edward Abraham, another of Florey's lab researchers, then made an important contribution to the purification process. Using chromatography - the technique of isolating a substance by drawing a mixture through various layers that act similar to filters - he separated the brown extract into bands of powder, one of which was yellowish, and 80 percent pure. It turned out that the penicillin the team had been using prior to this had been only one percent pure.

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What Penicillin Kills and How it Kills

Florey organized other workers to do a wide survey on penicillin's effects on harmful bacteria, to determine what species it inhibited. They were surprised that it killed a diverse group of bacteria known to be pathogens, although at varying doses. Tests showed that penicillin did not kill bacteria immediately on contact, meaning it was not an antiseptic, and they knew it was not an enzyme that dissolved them. Under a microscope, bacteria treated with penicillin became swollen and elongated, stopped dividing, and eventually burst or died.

Years later, it was found that penicillin works by binding to an enzyme that many bacteria use to build their cell walls. Penicillin has a characteristic β-lactam ring which mimics D-alanine-alanine in the cell wall structure. It destroys bacteria by interfering with cell wall development when it divides. The bacterium leaves holes that are disrupted by the penicillin and the result is the cell wall starts to get weak from all these holes it cannot fill up. The bacterium then elongates and weakens until it explodes under the pressure. There are two major types of bacteria, gram-positive and gram-negative. Penicillin is only effective against gram-positive bacteria because gram-negative bacteria have a protective protein layer that keeps the drug from interfering with the cell wall.

Penicillin's potency was even more stunning. When it was diluted to one part per million it still killed some types of bacteria, which meant it was twenty times more effective than the best drug to date, a sulfa drug. Penicillin was like no other drug because it treated so many diseases - syphilis, gonorrhea, childbed fever, septicemia, meningitis, scarlet fever, gas gangrene, anthrax, tetanus, rheumatic fever, lobar pneumonia, and diphtheria.

The Chemical Structure of Penicillin

Chain began with the hypothesis that penicillin was an enzyme. Chain tested his initial hypothesis by putting it through a cellophane filter. Penicillin went right through it, proving it to be much too small to be an enzyme, and Chain admitted that his "beautiful working hypothesis dissolved into thin air." But, rather than becoming discouraged, he became fascinated: "it became very interesting to find out which structural features were responsible for penicillin's instability. It was clear that we were dealing with a chemically very unusual substance."

Over time, scientists discovered that penicillin consisted of 27 atoms: 11 hydrogen, 9 carbon, 4 oxygen, 2 nitrogen atoms, and 1 sulphur atom. But there were two structures that could be constructed out of the atoms. It was in 1945 that Dr. Dorothy Crowfoot Hodgkin determined the structure, using X-ray analysis. The structures of three derivatives of benzylpenicillin were determined. Hodgkin found that penicillin has an unusual ring structure, with at least four isomers, and noticed it crystallized in different ways. Thus, it was a difficult crystallographic problem. Dr. Hodgkin came to believe that the core of the molecule consisted of three rings of carbon atoms and a nitrogen atom. This structure was assumed to be too unstable to exist independently, and it was the reason she had to study the sodium, potassium, and rubidium derivatives to discover this fact. This was a major step in the synthesis of chemically modified penicillin. Hodgkin received the Nobel Prize for this discovery in 1964.

Toxicity Tests

Florey and his team ran toxicity tests. One of the most fragile cells in the body is the leucocyte, a white blood cell that engulfs foreign bodies as part of the immune system. They tested penicillin on leucocyte cells in test tubes and were stunned to find it harmless, even when concentrated to one part per 500. Many other human tissue cells were also shown to be unaffected by penicillin. Penicillin has few common side effects in humans at standard doses, besides occasional upset stomach and diarrhea. The only major concern is that some people are allergic to it.

Mouse Tests Lead to Human Tests

Nine months after they had begun their work, Florey and his team were ready to perform a test on a living animal. At 11am, on Saturday, May 25, 1940, Florey and his assistant, Kent, injected eight white mice with a dose of virulent streptococci known to kill mice. At noon, they gave two mice injections of 5 ml of penicillin, and two others 10 ml. The other four were controls, so they received none. That afternoon, Florey, Heatley, and Kent watched the mice. Around six, Florey sent Kent home, and then gave the first two mice another dose. By 6:30pm, mice one, two and three looked fine. Mouse four looked so-so. The controls looked sick. The scientists went home to eat. At 10pm, Florey returned to give mice one and two another injection. The mice acted about the same as at six, so he went home. Heatley returned around eleven, and began marking down the times of death of the four control mice. The last one died at 3:28am. The next day Florey, Heatley and Chain met to go over the results. The four mice that had received penicillin were still alive. Florey, ever known for his understated manner, called Margaret Jennings, a coworker. "It looks like a miracle," he told her.

In the months that followed, they treated mice infected with different diseases, using fifty to seventy-five mice for each experiment. They learned that for some pathogens they had to keep penicillin in the blood for long periods of time. Because penicillin never lasted long in the blood, Florey and his team decided an intravenous drip was the best way to administer it.

Needing a much larger supply of penicillin to test it on humans, they published their results, but could not find a drug company to help them produce the drug. So, Florey had Heatley ramped up production, turning the laboratory into a fermentation plant with pipes and fermentation tanks tucked throughout their building. In early 1941, they began testing penicillin on humans. The drug worked well, but they never had enough; some patients even died after almost returning to good health. Thus, Florey flew through the dangerous war skies to America, to convince the U.S. government to get behind the production of penicillin. They did and, a couple of years later, there was enough to do large scale testing on humans, where it was shown to be a true miracle drug.

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Penicillin and the Antibiotic Explosion

Penicillin itself has also undergone vast development since Florey's day. In order to slow down the rapid
excretion of penicillin from the body, a search began for a molecule that would compete with penicillin in attaching to the organic acid transporters in the blood, which were ushering penicillin so quickly from the body. It was found that administering probenecid - a drug used to treat other ailments including gout - allowed penicillin to last much longer in the body, all the while killing bacteria.

The popularity of penicillin also led to a broad search for other natural substances with antibiotic properties. In 1944, Selman Waksman, the man who coined the term antibiotic, discovered streptomycin, which treated tuberculosis, long a scourge of humankind. Abraham and Heatley, still working under Florey, went on to develop the cephalosporins, a class of antibiotics that kill some penicillin-resistant bacteria. Today, more than 10,000 substances with antibiotic properties are known, many of which have been used to save millions of additional lives.

In 1957, John C. Sheehan, of MIT, synthesized penicillin, making the fermentation process Heatley so labored over unnecessary. And in the 1960s, the Beecham Research Laboratories in Surrey, England, patented the synthesized penicillin derivatives ampicillin and amoxicillin, which made good absorption of oral penicillin possible in pill form. Fifty years after the advent of penicillin, amoxicillin was still the most prescribed drug in the United States, constituting 3.8 percent of all the prescriptions in the country in 1994.

Bacterial Resistance to Penicillin

Even though penicillin was a true miracle drug, it wasn't long before some bacteria became resistant to it. Bacterial drug resistance occurs by evolution through mutation. Individual bacteria with mutations that allow them to survive an antibiotic thrive and replace those without resistance. For instance, some populations of staph a. were observed in 1947 producing an enzyme that would break apart the beta-lactam ring in penicillin, which is the very structure that gives penicillin its antibiotic potency. Bacterial evolution can occur rapidly. Bacteria (and many viruses) can reproduce as fast as every 20 minutes. This equals 3 times an hour, 72 times a day, 26,280 times a year - 525,600 times faster than a human's normal reproductive cycle of around 20 years. In addition, an infection consists of many, many bacteria. When an antibiotic is taken, it may kill billions of bacteria. But, if only a few with mutations survive, grow, and multiply, they will quickly repopulate, carrying with them their resistant characteristic.

Studies of bacterial resistance demonstrated that not only can bacteria pass mutated genes along to their offspring by asexual reproduction, but also through horizontal transfer, known as bacterial conjugation. Once a mutated gene exists in a bacterial population, it can be passed to its neighbors by the transfer of plasmids, which are strands of DNA independent from the chromosomal DNA. Soon, a whole colony of bacteria can have its own life-saving gene which can be passed on to their progeny.

Scientists have worked diligently to develop new antibiotics to replace those that become obsolete due to evolved resistance. But, by the late 1990s, half of all Staph a. bacteria was resistant to penicillin, methicillin, tetracycline, and erythromycin. Two million people in the U.S. get infected in hospitals each year, according to the National Institutes of Health. Seventy percent of the bacteria that cause these infections are resistant to at least one antibiotic. Of those infected, 90,000 die, an increase of nine percent in the past ten years. Bacteria are as clever at developing resistance to current antibiotics as scientists are at developing new ones, and the battle against infection, begun in 1942 with the development of penicillin, is far from over.

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Personal Information

Early Life

Walter Florey was born on September 24, 1898, in Adelaide, South Australia, the youngest of five children and the only son born to Joseph and Bertha Mary Florey. He grew to be handsome, if short (5'7"), an excellent athlete, competitive to a fault, and spiced with a fiery temper. His early education began at St. Peter's Collegiate School in Adelaide, where he acquired the nickname "Floss." In class he won prizes in science competitions and was most intrigued by chemistry.

The school's headmaster insisted there was no future for a chemist in colonial Australia, so Florey instead went off to pursue medicine at Adelaide University. It was there he meet Ethel Reed, while working on the Adelaide Medical Students' Society Review, whom he would later marry. Florey was awarded the Rhodes Scholarship to Magdalen College, Oxford, leading him to study at Cambridge as a John Lucas Walker Student. Then, in 1925, on a Rockefeller Traveling Fellowship, he visited the United States for a year. Afterwards, Florey returned to receive his Ph.D. from Gonville and Caius College, Cambridge.

Education

1921 - M.B., B.S., Adelaide University
1924 - B.Sc. and M.A., Magdalen College, Oxford
1927 - Ph.D., Gonville and Caius College, Cambridge

Family

Wife - Ethel Reed
Son - Charles du Vé
Daughter - Paquita Mary Joanna

Howard Florey's Life: A Timeline

1898 - born on Sept. 24, in Adelaide, Australia
1921 - M.B., B.S., Adelaide University
1924 - B.Sc. and M.A., Magdalen College, Oxford
1925 - Florey won a Rockefeller grant to study in the U.S.
1926 - married Ethel Reed
1926 - Fellowship at Gonville and Caius College, Cambridge
1927 - Ph.D., Gonville and Caius College, Cambridge
1927 - Huddersfield Lecturer in Special Pathology at Cambridge
1929 - daughter, Paquita Mary Joanna
1931 - chair of pathology, Sheffield University
1934 - son, Charles du Vé
1935 - chair of pathology, Oxford University
1938 - Began researching naturally occurring antibacterial substances
1944 - Knight Bachelor
1944 - Nuffield Visiting Professor to Australia and New Zealand
1945 - The Nobel Prize in Physiology or Medicine
1946 - Honorary Fellow of Gonville and Caius College, Cambridge
1952 - Honorary Fellow of Magdalen College, Oxford
1960 - President of the Royal Society
1962 - Provost of The Queen's College, Oxford
1968 - Feb. 21, died of a heart attack


Scientific Discovery Timeline

1928 - Fleming discovers that the penicillium mold creates an antibacterial substance.
1939 - Florey obtains financing of a penicillin study through a grant from the Rockefeller Foundation.
1939 - Florey's friend suggests that adding brewer's yeast cuts the fermentation time in half.
1940 - Chain discovers that adding ether helps to isolate penicillin.
1940 - Heatley discovers how to pull penicillin back out of the ether.
1940 - Chain uses freeze drying to get penicillin into a useable form.
1940 - May 25, mice testing begins.
1941 - Edward Abraham uses chromatography to improve purity from 1% to 80%.
1941 - January, first human testing on Elva Akers.
1941 - June 27, Florey and Heatley go to the U.S. to elicit help in mass producing penicillin.
1941 - Switched to corn steep liquor instead of yeast in the fermentation process.
1941 - "Moldy Mary" Hunt finds a more potent strain of penicillin on a cantaloupe.
1942 - January, extensive human testing begins under the direction of Ethel Florey, Howard's wife.
1943 - Resistant strains of Staphylococcus aureus bacteria emerge.
1943 - Commercial production of penicillin begins.
1944 - D-day, June 6, enough penicillin available to treat all 40,000 men wounded in the Normandy invasion.
1944 - Australia begins first use of penicillin with the public.
1945 - Dorothy Hodgkin discovers penicillin's chemical structure.
1957 - John Sheehan first synthesizes penicillin.
1961 - Beecham Research Laboratories patents ampicillin and amoxicillin, the first pills of penicillin.


 

Recommended Books about the Science of Penicillin




Books by Howard Florey

 



Books about Florey

Williams, Trevor. Howard Florey: Penicillin and After. Oxford University Press, 1984.

Bickel, Lennard. Howard Florey: The Man Who Made Penicillin (Australian Lives series). Melbourne University Publishing, 1996.

MacFarlane, Gwyn. Howard Florey: The Making of a Great Scientist. Oxford University Press, 1979. 

Woodward, Billy, Shurkin, Joel and Gordon, Debra. Scientists Greater than Einstein: The Biggest Lifesavers of the Twentith Century. Linden Publishing, 2009.



Awards

The Nobel Prize in Physiology or Medicine, 1945
Lister Medal, Royal College of Surgeons, 1945
Berzelius Medal in Silver, Swedish Medical Society 1945
Albert Medal, Royal Society of Arts, 1946
Medal in therapeutics from the Worshipful Society of Apothecaries, 1946
Royal Society of Medicine Gold Medal, 1947
USA Medal of Merit, 1948
Royal Medal, 1951
British Medical Association Gold Medal, 1964
Lomonosov Medal, USSR Academy of Sciences, 1965


 

Major Academic Papers

Penicillin as a chemotherapeutic Agent. Chain, E., Florey, H.W., Gardner, A.D., Heatley, N.G., Jennings,.B.M., Orr-Ewing, J., Sanders, A.G., Lancet. Volume 236, Issue 6104, 24 August 1940, p 226-228. Originally published as Vol. 2, Issue 6104.



Curriculum Vitae

 



Links to Science and Related Information on the Subject

How penicillin kills bacteria and how bacteria fight back
http://www.rpc.msoe.edu/cbm/smartteams/pdf/2007/mwp2007.pdf

Very cool interactive 3D model
http://www.3dchem.com/molecules.asp?ID=250#

Time lapse video of penicillium mold growth

Exploding Bacteria!
http://www.cellsalive.com/pen.htm

MSDS of penicillin G
http://msds.chem.ox.ac.uk/PE/penicillin_G_sodium_salt.html

History of antibiotics
http://inventors.about.com/od/pstartinventions/a/Penicillin_2.htm

Penicillin allergy
http://www.mayoclinic.com/health/penicillin-allergy/DS00620

Penicillin cartoons
http://www.cartoonstock.com/directory/p/penicillin.asp
Florey, Howard Biography http://nobelprize.org/nobel_prizes/medicine/laureates/1945/florey-bio.html

How Penicillin Kills Bacteria http://www.rpc.msoe.edu/cbm/smartteams/pdf/2007/mwp2007.pdf

Penicillin G drug information http://www.nlm.nih.gov/medlineplus/druginfo/meds/a685013.html

Penicillin G http://www.drugs.com/pro/penicillin-g.html

Dr. Dorothy Crowfoot Hodgkin http://nobelprizes.com/nobel/chemistry/dch.html

Wine Quotes http://www.800wine.com/winequotes.cfm

Amazing Facts about Penicillin http://66.39.48.152/tallpoppies/florey/explorer/penicillin/63ex.html

Brainy Quote http://www.brainyquote.com/quotes/quotes/k/katherined278705.html

Don't Quote Me http://www.dontquoteme.com/feature/topten/InventorQuotes.jsp

Florey and Chain http://www.chemheritage.org/educationalservices/pharm/antibiot/readings/flocha.htm

Florey http://www.aim25.ac.uk/cgi-bin/search2?coll_id=5981&inst_id=18



Sources/References

Penicillin as a chemotherapeutic Agent. Chain, E., Florey, H.W., Gardner, A.D., Heatley, N.G., Jennings,.B.M., Orr-Ewing, J., Sanders, A.G., Lancet. Volume 236, Issue 6104, 24 August 1940, p 226-228. Originally published as Vol. 2, Issue 6104.