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space, renewing the broth beneath the surface of the mold. A team of "penicillin girls" was employed, at 2 a week,
to inoculate and generally look after the fermentation. In effect, the Oxford laboratory was being turned into a
penicillin factory.
Meanwhile, biochemist Norman Heatley extracted penicillin from huge volumes of filtrate coming off the
production line by extracting it into amyl acetate and then back into water, using a countercurrent system. Edward
Abraham, another biochemist who was employed to help step up production, then used the newly discovered
technique of alumina column chromatography to remove impurities from the penicillin prior to clinical trials.
In 1940, Florey carried out vital experiments, showing that penicillin could protect mice against infection from
deadly Streptococci. Then, on February 12, 1941, a 43-year old policeman, Albert Alexander, became the first
recipient of the Oxford penicillin. He had scratched the side of his mouth while pruning roses, and had developed a
life-threatening infection with huge abscesses affecting his eyes, face, and lungs. Penicillin was injected and within
days he made a remarkable recovery. But supplies of the drug ran out and he died a few days later. Better results
followed with other patients though and soon there were plans to make penicillin available for British troops on the
battlefield.
War-time conditions made industrial production of penicillin difficult. A number of British companies, including
Glaxo (now GlaxoSmithKline) and Kemball Bishop, a London firm later bought by Pfizer, took up the challenge.
~~~
This landmark work began in 1938 when Florey, who had long been interested in the ways that bacteria and mold
naturally kill each other, came across Flemings paper on the penicillium mold while leafing through some back
issues of The British Journal of Experimental Pathology. Soon after, Florey and his colleagues assembled in his
well-stocked laboratory. They decided to unravel the science beneath what Fleming called penicilliums
antibacterial action.
One of Floreys brightest employees was a biochemist, Dr. Ernst Chain, a Jewish German migr. Chain was an
abrupt, abrasive and acutely sensitive man who fought constantly with Florey over who deserved credit for
developing penicillin. Despite their battles, they produced a series of crude penicillium-mold culture fluid extracts.
During the summer of 1940, their experiments centered on a group of 50 mice that they had infected with deadly
streptococcus. Half the mice died miserable deaths from overwhelming sepsis. The others, which received penicillin
injections, survived.
It was at that point that Florey realized that he had enough promising information to test the drug on people. But the
problem remained: how to produce enough pure penicillin to treat people. In spite of efforts to increase the yield
from the mold cultures, it took 2,000 liters of mold culture fluid to obtain enough pure penicillin to treat a single
case of sepsis in a person.
In September 1940, an Oxford police constable, Albert Alexander, 48, provided the first test case. Alexander nicked
his face working in his rose garden. The scratch, infected with streptococci and staphylococci, spread to his eyes and
scalp. Although Alexander was admitted to the Radcliffe Infirmary and treated with doses of sulfa drugs, the
infection worsened and resulted in smoldering abscesses in the eye, lungs and shoulder. Florey and Chain heard
about the horrible case at high table one evening and, immediately, asked the Radcliffe physicians if they could try
their purified penicillin.
After five days of injections, Alexander began to recover. But Chain and Florey did not have enough pure penicillin
to eradicate the infection, and Alexander ultimately died.
Another vital figure in the lab was a biochemist, Dr. Norman Heatley, who used every available container, bottle and
bedpan to grow vats of the penicillin mold, suction off the fluid and develop ways to purify the antibiotic. The
makeshift mold factory he put together was about as far removed as one could get from the enormous fermentation
tanks and sophisticated chemical engineering that characterize modern antibiotic production today.
In the summer of 1941, shortly before the United States entered World War II, Florey and Heatley flew to the United
States, where they worked with American scientists in Peoria, Ill., to develop a means of mass producing what
became known as the wonder drug.
Aware that the fungus Penicillium notatum would never yield enough penicillin to treat people reliably, Florey and
Heatley searched for a more productive species.
One hot summer day, a laboratory assistant, Mary Hunt, arrived with a cantaloupe that she had picked up at the
market and that was covered with a pretty, golden mold. Serendipitously, the mold turned out to be the fungus
Penicillium chrysogeum, and it yielded 200 times the amount of penicillin as the species that Fleming had described.
Yet even that species required enhancing with mutation-causing X-rays and filtration, ultimately producing 1,000
times as much penicillin as the first batches from Penicillium notatum.
In the war, penicillin proved its mettle. Throughout history, the major killer in wars had been infection rather than
battle injuries. In World War I, the death rate from bacterial pneumonia was 18 percent; in World War II, it fell, to
less than 1 percent.
From January to May in 1942, 400 million units of pure penicillin were manufactured. By the end of the war,
American pharmaceutical companies were producing 650 billion units a month.
Ironically, Fleming did little work on penicillin after his initial observations in 1928. Beginning in 1941, after news
reporters began to cover the early trials of the antibiotic on people, the unprepossessing and gentle Fleming was
lionized as the discoverer of penicillin. And much to the quiet consternation of Florey, the Oxford groups
contributions were virtually ignored.
~~~
Life in the 1940's centered around World War II. Men were going off to war and women were doing the men's jobs,
They did what they could have not done when the men were there, such as play a professional sports or do jobs that
men usually took . Many soldiers suffered from war wounds and often died from them. Some were lucky to survive
long enough to see their family, friends, and spouses; but they died eventually from the infections. Of course, this
could have happened to anyone in the 1940's or before. A simple cut from knife could lead to your death because
there were no antibiotics to stop bacteria from growing and entering your body. Due to this, people were not really
expected to live past the age of 60 or 68. People could have also died from surgeries. People who had surgeries had a
higher chance of getting an infection than those of us today because, again, there was nothing to stop bacteria to
grow. People began to collect scrap metals to help the war effort, especially after the tragic bombing of Pearl Harbor.
The center of everyone's life in the world was World War II, and people all over the globe were affected by the
outcomes of the war.
Penicillin was accidentally invented by Alexander Fleming. Around August or September of 1928 Sir Alexander
Fleming started growing staphylococcus bacteria in a culture plate. He left it untouched for a while and he had
accidentally let it grow mold. He noticed that the mold had been killing the bacteria. Instead of throwing out the
bacteria like any other person would, he began to study the mold and bacteria. Fleming realized that the mold is
called Penicillium notatum, hence the name penicillin. At first, Fleming thought of this discovery as useless because
it was very hard to produce, meaning it can not be easily mass produced to be distributed among people. He
eventually gave up, but his work was later used to create the first mass produced antibiotic.
In the late 1930's, Howard Florey and Ernst Chain found Flemming's research and helped to develop penicillin.
They discovered an easier way to purify penicillin. When Florey and Chain first tested penicillin, they did not use
humans. They actually used eight mice. Four of the mice were given penicillin and four were not. Six mice died
and two given the medicine survived. Then, Florey and Chain tested penicillin on a human.On February 1, 1941, a
policeman with a severe case of staphylococcus was given the antibiotic. The penicillin ran out and the man died,
but he did get much better over the time he had penicillin. Chain and Florey soon discovered that the corn steep
liquor could be used to mass produce penicillin. On top of that Ernest Chain and Howard Florey convinced a big
company to produce and sell penicillin. This event plus the discovery of using corn steep liquid really helped to
launch the reign and mass impacts of penicillin. This was the era of the "wonder drug." Penicillin was a huge
accomplishment and saved many lives.
~~~
Penicillin's ability to cure people of many once-fatal bacterial infections has saved so many lives that it is easy to
understand why it was once called a "miracle drug".
Antibiotics are chemicals, effective at very low concentrations, created as part of the life process of one organism,
which can kill or stop the growth of a disease-causing microbe--a germ. In 1929, Alexander Fleming, a doctor and
researcher at St. Mary's Hospital in London, England, published a paper on a chemical he called "penicillin", which
he had isolated from from a mold, Penicillium notatum. Penicillin, Fleming wrote, had prevented the growth of a
neighboring colony of germs in the same petri dish. Dr. Fleming was never able to purify his samples of penicillin,
but he became the first person to publish the news of its germ-killing power. Howard Florey, Ernst Chain and
Norman Heatley expanded on Fleming's work in 1938, at Oxford University. They and their staff developed methods
for growing, extracting and purifying enough penicillin to prove its value as a drug.
World War II (1939-1945) had begun by the time their research was showing results. The main research and
production was moved to the United States in 1941, to protect it from the bombs pounding England. Work began on
how to grow the mold efficiently to make penicillin in the large quantities that would be needed for thousands of
soldiers. As the destruction of the war grew, so did interest in penicillin in laboratories, universities and drug
companies on both sides of the Atlantic. The scientists knew they were in a race against death, because an infection
was as likely to kill a wounded soldier as his wound.
Creating the right environment for growth was the first step in producing enough penicillin to be used as a drug. In
Oxford, experiments showed that Penicillium notatum grew best in small shallow containers on a broth of nutrients.
Penicillium need lots of air. In the United States, it was discovered that huge "deep fermentation" tanks could be
used if sterilized air was pumped continually through the tanks. Production increased even more when corn steep
liquor, a thick, sticky by-product of corn processing, was added to the tanks. Corn steep liquor contained
concentrated nutrients that increased the yield 12-20 times. Formerly considered a waste material, corn steep liquor
became a crucial ingredient in the large-scale production of penicillin.
Scientists were also determined to find another strain of Penicillium that might grow better in the huge deep
fermentation tanks. Army pilots sent back soil samples from all over the world to be tested for molds. Residents of
Peoria, Illinois, were encouraged to bring moldy household objects to the local U.S. Department of Agriculture
laboratory, where penicillin research was being conducted. Laboratory staff members also kept an eye out for
promising molds while grocery shopping or cleaning out their refrigerators.
In 1943, laboratory worker Mary Hunt brought in an ordinary supermarket cantaloupe infected with a mold that had
"a pretty, golden look." This Penicillium species, Penicillium chrysogenum grew so well in a tank that it more than
doubled the amount of penicillin produced. The deep fermentation method, the use of corn steep liquor and the
discovery of P. chrysogenumby Mary Hunt made the commercial production of penicillin possible. Researchers
continued to find higher-yielding Penicillium molds, and also produced higher yielding strains by exposing molds to
x-rays or ultraviolet light.
Penicillin kills by preventing some bacteria from forming new cell walls. One by one, the bacteria die because they
cannot complete the process of division that produces two new "daughter" bacteria from a single "parent" bacterium.
The new cell wall that needs to be made to separate the "daughters" is never formed.
Some bacteria are able to resist the action of antibiotic drugs, including penicillin. Antibiotic resistance occurs
because not all bacteria of the same species are alike, just as people in your own family are not exactly alike.
Eventually, the small differences among the bacteria often mean that some will be able to resist the attack of an
antibiotic. If the sick person's own defenses can not kill off these resistant bacteria, they will multiply. This
antibiotic-resistant form of a disease can re-infect the patient, or be passed on to another person.
Taking antibiotics for viral illnesses like colds can also cause antibiotic resistant bacteria to develop. Antibiotics
have no effect on viruses, but it will kill off harmless and even the beneficial bacteria living in the patient's body.
The surviving resistant bacteria, free from competition, will live and multiply and may eventually cause disease.
Patients with bacterial infections, who don't finish their antibiotic prescriptions completely, also allow resistant
bacteria to develop. This happens because a small number of semi-resistant bacteria, which needed the full course of
antibiotics to kill them, survive. Instead of being a small part of the bacteria causing an infection, the more resistant
bacteria take over when sensitive bacteria are killed by the antibiotic.
Today, in the United States, deaths by infectious bacterial diseases are only one-twentieth of what they were in 1900,
before any antibiotic chemicals had been discovered. The main causes of death today are what are referred to as "the
diseases of old age": heart disease, kidney disease and cancer. We would be shocked to hear of someone dying from
an infection that started in a scratch, but, before antibiotics like penicillin, it was common for people to die from
such infections.
Humans can slow the creation of antibiotic resistant diseases by understanding the uses and limits of antibiotics.
Take all of an antibiotic, and only take them when prescribed by a doctor. Research to develop new antibiotics to
treat resistant bacteria continues, but research takes time. Time is running out because the world's biodiversity is
decreasing--the source of half of our disease-fighting chemicals.
An example of the importance of preserving the world's biodiversity occurred in 1996, in New York state. Students
at Cornell University collected a fungus that finally made it possible to identify the two very different life stages of
the mold that produces the drug cyclosporin. Cyclosporin prevents the rejection of transplanted organs. Without it,
transplant operations would be impossible. Knowing the full life history of the cyclosporin-producing fungus may
make it easier to find related molds. Even people who see no special beauty or value in the world's biodiversity may
one day benefit from the currently unknown and powerful substances, produced by fungi and other microbes, that
are waiting for discovery in familiar places.
~~~
How It Works
Penicillin works by preventing cells from dividing. It does not allow them to synthesize cell wall, and thus when the
cells attempt to duplicate, they rupture and end up killing themselves. Because penicillin has such a strong focus on
a bacterias cell wall, it is far more effective on Gram-positive organisms. When a Gram-positive organism attempts
to duplicate itself, it must create more cell wall and split off, the penicillin causes there not to be any new cell wall,
and instead of duplicating, the cell will simply rupture, effectively killing it.
~~~
The story of penicillin - the first antibiotic used successfully to treat people with serious infectious diseases - begins
with a bit of luck. Alexander Fleming, a British scientist, noticed in 1928 that mould had prevented the growth of
bacteria in his lab. But the main plot of the story involves the rediscovery of penicillin 10 years later by an
Australian scientist born one hundred years ago this year. Howard Florey and his dedicated team's systematic,
detailed work transformed penicillin from an interesting observation into a life saver.
Emma Burkervisc used to be the tea lady at the Australian National University's John Curtin School of Medical
Research (Howard Florey played a crucial role in the establishment of the School and University later in his life).
Emma's life was saved by penicillin in a German refugee camp after World War II. Imagine how she felt many years
later, bumping into Florey in the corridors where she worked - the man who made the supply of penicillin possible.
Imagine how you'd feel if you met someone who saved your life; and think of Florey and his team's impact on the
world.
Breaking the Mould
Florey gathered a team of scientists at Oxford University in Britain in the 1930s, when working together on
scientific discoveries as a group was not at all common. Nowadays scientists work together all the time, but Florey
realised that science had reached a point where a team of specialists was needed - the job was too big for one person.
His team commenced a careful investigation of the properties of anti-bacterial substances that are produced by
mould. One member of the team, Ernst Chain, found an article about Alexander Fleming's work while flicking
through a medical journal, and this prompted them to begin looking at penicillin.
Individual members of the group concentrated their attention on areas in which they had the most knowledge, but
they often met to exchange ideas. Chain worked on purifying penicillin with Edward Abraham. Norman Heatley
improvised methods for extracting penicillin using ether and bedpans (see 'penicillin production' below). A. D.
Gardner and Jena Orr-Ewing studied how penicillin reacted with other organisms. Howard Florey looked with
Margaret Jennings at the impact of penicillin on animals. Ethel Florey later worked with her husband on clinical
trials of penicillin.
In May, 1940 they performed one of the most important medical experiments in history. The work was so urgent that
they came in to begin the experiment on the weekend, and on Saturday 25 May, Florey's team tested penicillin on
eight mice injected with a lethal dose of streptococci bacteria. Four of the mice were treated with penicillin, while
four were used as controls. By the next day, the treated mice had recovered and the untreated mice were dead. In the
early days of World War II, the lives of eight mice may seem insignificant. But their rescue by penicillin led to the
treatment of Allied soldiers as early as D-Day, in June 1944, and probably influenced the outcome of the war.
The First Patient
The results were so exciting Florey knew that it was time to test the drug on humans. The first patient in 1941 had
been scratched by a rose thorn. Albert Alexander's whole face, eyes and scalp had swollen. He had already had an
eye removed and abscesses drained; even his remaining eye had to be lanced to relieve the pain of the swelling. He
was given penicillin, and within a day he began to recover. But Florey's team didn't have enough of the drug to see
the patient through to a full recovery. Their efforts to recycle the penicillin by extracting it from his urine failed, and
he unfortunately had a re-lapse and died. Because of the awful experience, the team then concentrated their efforts
on sick children, who did not require such large quantities.
In 1943 Florey travelled to North Africa to test the effects of penicillin on wounded soldiers. His trials were seen as
a miracle. Instead of amputating wounded limbs or simply leave them to heal, he suggested soldiers' wounds be
cleaned and sewn up, and that the patients then be given penicillin. Thanks to Florey and his team, the drug was
available to treat Allied troops by the end of World War II. It has since revolutionised medical science, saving
millions of lives.
Before Penicillin
How many times have you accidentally pricked your finger on a rose thorn, or perhaps a sewing needle? Nowadays,
if the wound became infected you'd be cured almost immediately. But before the second half of this century, you
could have been in big trouble. Infections were feared then as cancer is feared today. Your glands would swell up
and require lancing to release the pus. A surgeon might even have to amputate your arm in an attempt to save your
life. This was the nightmare of many infectious diseases before Howard Florey developed penicillin.
Setting the Stage for Penicillin
Three thousand years before penicillin, moulds and fermented materials had been used to cure various skin
infections, although without an understanding of how they actually worked. But it wasn't until the late 1800s that
scientific studies of antibiotics began. French chemist Louis Pasteur, after discovering that infectious diseases are
spread by bacteria, observed that mould inhibited the growth of anthrax (an infectious disease spread from animals
to humans). British surgeon Joseph Lister noted that samples of urine contaminated with mould didn't allow bacteria
to grow, but he was unable to identify the substance in the mould. French medical student Ernest Duchesne
successfully tested a substance from mould that inhibited bacterial growth in animals, but died at an early age in
1912, never seeing the world's acceptance and use of his important discovery.
After World War I, Alexander Fleming was conducting an experiment with bacteria when a tear fell from his eye
into a culture plate. He later noticed that a substance in his tear (which he named lysozyme) killed the bacteria, but
was harmless to the body's white blood cells. Years later, Fleming was doing research on the flu when a similar
coincidence occurred. While he was on holidays, a bit of mould had fallen into a discarded culture plate containing
bacteria, forming a clear patch. When he returned he recognised this pattern from his previous experience with
lysozyme. He concluded that the mould was producing an antibiotic substance and named the antibiotic penicillin,
after the Penicillium mould that produced it.
His discovery was an amazing piece of luck. If Fleming hadn't left a petri dish of bacteria on his bench when he
went on holidays; if he had properly disinfected the dish; if the weather had been different from the ideal conditions
for bacteria and mould growth in the laboratory; and especially if Fleming hadn't the experience to recognise the
importance of the observation, penicillin may not have been discovered as an antibiotic.
But Fleming couldn't extract the bacteria-killing substance, so he couldn't try it as a treatment for general infections.
He moved on to other research - leaving Howard Florey and his team to pave the way for penicillin's use as a
lifesaver more than a decade later.
Fabulous Fungus
Penicillin was the first naturally occurring antibiotic discovered (Prontosil, the first chemical used to cure certain
infectious diseases, had been discovered in 1933 but had serious side effects). There are now more than 60
antibiotics, which are substances that fight bacteria, fungi and other microbes harmful to humans - the word means
against (anti) life (bio).
An antibiotic is a drug produced by microbes. Penicillin is obtained in a number of forms from Penicillium moulds.
Penicillin G is the most widely used form, and is the one that killed bacteria during Duchesne's work in 1896,
Fleming's work in 1928 and Florey's work in 1939.
Bacteria reproduce by dividing to produce two new cells. They enlarge to about twice their size before the DNA
chromosome is copied. The two new chromosomes move apart and a cell wall forms between them. But if penicillin
is around the new cell wall won't be able to form. It doesn't harm old bacterial cell walls, it just stops new ones
forming. This means the bacteria can't reproduce, so the disease can't spread.
Natural penicillin is administered by injection, because if it's swallowed stomach acids destroy the drug before it
reaches the bloodstream. One shot of penicillin these days is more than the entire amount used by Florey's team in
all its clinical trials! About one in 10 people is allergic to penicillin, showing symptoms ranging from minor rashes
to serious breathing difficulties. If you're allergic to penicillin, there are now other antibiotics that can be taken as a
substitute.
Penicillin Production
Florey's team worked under difficult circumstances with a lack of funding and equipment, but ensured penicillin
production grew from the manufacture of a scarce and very impure brown powder to the commercial production of a
purified and powerful antibiotic.
At first penicillin was made using old dairy equipment. Hospital bedpans were used to grow mould. Liquid
containing penicillin was drained from beneath the growing mould and filtered through parachute silk on
bookshelves. But the team needed drug companies to help it produce the large amounts required for test patients.
Companies in Britain were unable to help out on a large scale because of the war, so Howard Florey and Norman
Heatley took a dangerous flight to the United States in a blacked-out plane across the Atlantic. The trip was against
the wishes of Ernst Chain, who wanted to first patent their ideas in Britain. This would have made the team very rich
indeed, but it was thought in Britain at the time that patenting medical discoveries was unethical.
Florey explained his penicillin-making methods to people in the US, and there happened to be a Department of
Agriculture laboratory looking for a new use for a thick liquid that was a by product from the corn-milling process.
When this liquid was used, 10 times the amount of penicillin was able to be produced than before. Mary Hunt,
known as Mouldy Mary for her enthusiasm in finding new sources of mould, then found mould growing in
cantaloupe (rockmelon) was twice as successful again at producing penicillin.
By late 1943, mass production of the drug had commenced - only four years after the first mouse experiments and in
spite of the war, a sign of Florey's persistence and determination. By the end of the war, many laboratories were
manufacturing the drug, including the Merck, Squibb and Pfizer companies in the US and the Commonwealth
Serum Laboratories in Australia. In fact, Australia was the first country that made the drug available for civilian use.
However, several strains of bacteria became resistant to penicillin after a few years, through mutation of the cells. To
overcome this problem, scientists in the 1950s made artificial penicillin by chemically changing natural penicillin.
Resistant bacteria multiply when non-resistant bacteria die. Hospitals in Australia and around the world are now
seeing the arrival of antibiotic-resistant bacteria due to the overuse of antibiotics, exposing the very young, very old
and very sick people to infections and diseases.