01 October 2009

Penicillin



The invention: The first successful and widely used antibiotic
drug, penicillin has been called the twentieth century’s greatest
“wonder drug.”
The people behind the invention:
Sir Alexander Fleming (1881-1955), a Scottish bacteriologist,
cowinner of the 1945 Nobel Prize in Physiology or Medicine
Baron Florey (1898-1968), an Australian pathologist, cowinner
of the 1945 Nobel Prize in Physiology or Medicine
Ernst Boris Chain (1906-1979), an émigré German biochemist,
cowinner of the 1945 Nobel Prize in Physiology or Medicine
The Search for the Perfect Antibiotic
During the early twentieth century, scientists were aware of antibacterial
substances but did not know how to make full use of them
in the treatment of diseases. Sir Alexander Fleming discovered penicillin
in 1928, but he was unable to duplicate his laboratory results
of its antibiotic properties in clinical tests; as a result, he did not recognize
the medical potential of penicillin. Between 1935 and 1940,
penicillin was purified, concentrated, and clinically tested by pathologist
Baron Florey, biochemist Ernst Boris Chain, and members
of their Oxford research group. Their achievement has since been regarded
as one of the greatest medical discoveries of the twentieth
century.
Florey was a professor at Oxford University in charge of the Sir
William Dunn School of Pathology. Chain had worked for two years
at Cambridge University in the laboratory of Frederick Gowland
Hopkins, an eminent chemist and discoverer of vitamins. Hopkins
recommended Chain to Florey, who was searching for a candidate
to lead a new biochemical unit in the Dunn School of Pathology.
In 1938, Florey and Chain formed a research group to investigate
the phenomenon of antibiosis, or the antagonistic association between
different forms of life. The union of Florey’s medical knowledge
and Chain’s biochemical expertise proved to be an ideal combination for exploring the antibiosis potential of penicillin. Florey
and Chain began their investigation with a literature search in
which Chain came across Fleming’s work and added penicillin to
their list of potential antibiotics.
Their first task was to isolate pure penicillin from a crude liquid
extract. A culture of Fleming’s original Penicillium notatum was
maintained at Oxford and was used by the Oxford group for penicillin
production. Extracting large quantities of penicillin from the
medium was a painstaking task, as the solution contained only one
part of the antibiotic in ten million. When enough of the raw juice
was collected, the Oxford group focused on eliminating impurities
and concentrating the penicillin. The concentrated liquid was then
freeze-dried, leaving a soluble brown powder.
Spectacular Results
In May, 1940, Florey’s clinical tests of the crude penicillin proved
its value as an antibiotic. Following extensive controlled experiments
with mice, the Oxford group concluded that they had discovered
an antibiotic that was nontoxic and far more effective against
pathogenic bacteria than any of the known sulfa drugs. Furthermore,
penicillin was not inactivated after injection into the bloodstream
but was excreted unchanged in the urine. Continued tests
showed that penicillin did not interfere with white blood cells and
had no adverse effect on living cells. Bacteria susceptible to the antibiotic
included those responsible for gas gangrene, pneumonia,
meningitis, diphtheria, and gonorrhea. American researchers later
proved that penicillin was also effective against syphilis.
In January, 1941, Florey injected a volunteer with penicillin
and found that there were no side effects to treatment with the
antibiotic. In February, the group began treatment of Albert Alexander,
a forty-three-year-old policeman with a serious staphylococci
and streptococci infection that was resisting massive doses of
sulfa drugs. Alexander had been hospitalized for two months after
an infection in the corner of his mouth had spread to his face,
shoulder, and lungs. After receiving an injection of 200 milligrams
of penicillin, Alexander showed remarkable progress, and for the
next ten days his condition improved. Unfortunately, the Oxford production facility was unable to generate enough penicillin to
overcome Alexander’s advanced infection completely, and he died
on March 15. A later case involving a fourteen-year-old boy with
staphylococcal septicemia and osteomyelitis had a more spectacular
result: The patient made a complete recovery in two months. In
all the early clinical treatments, patients showed vast improvement,
and most recovered completely from infections that resisted
all other treatment.
Impact
Penicillin is among the greatest medical discoveries of the twentieth
century. Florey and Chain’s chemical and clinical research
brought about a revolution in the treatment of infectious disease.
Almost every organ in the body is vulnerable to bacteria. Before
penicillin, the only antimicrobial drugs available were quinine, arsenic,
and sulfa drugs. Of these, only the sulfa drugs were useful for
treatment of bacterial infection, but their high toxicity often limited
their use. With this small arsenal, doctors were helpless to treat
thousands of patients with bacterial infections.
The work of Florey and Chain achieved particular attention because
ofWorldWar II and the need for treatments of such scourges
as gas gangrene, which had infected the wounds of numerous
World War I soldiers. With the help of Florey and Chain’s Oxford
group, scientists at the U.S. Department of Agriculture’s Northern
Regional Research Laboratory developed a highly efficient method
for producing penicillin using fermentation. After an extended search,
scientists were also able to isolate a more productive penicillin
strain, Penicillium chrysogenum. By 1945, a strain was developed that
produced five hundred times more penicillin than Fleming’s original
mold had.
Penicillin, the first of the “wonder drugs,” remains one of the
most powerful antibiotic in existence. Diseases such as pneumonia,
meningitis, and syphilis are still treated with penicillin. Penicillin
and other antibiotics also had a broad impact on other fields of medicine,
as major operations such as heart surgery, organ transplants,
and management of severe burns became possible once the threat of
bacterial infection was minimized.Florey and Chain received numerous awards for their achievement,
the greatest of which was the 1945 Nobel Prize in Physiology
or Medicine, which they shared with Fleming for his original discovery.
Florey was among the most effective medical scientists of
his generation, and Chain earned similar accolades in the science of
biochemistry. This combination of outstanding medical and chemical
expertise made possible one of the greatest discoveries in human
history.

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