Penicillin (Inventions)

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 emigre 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 staphylo-cocci 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


Sir Alexander Fleming

In 1900 Alexander Fleming (1881-1955) enlisted in the London Scottish Regiment, hoping to see action in the South African (Boer) War then underway between Great Britain and South Africa’s independent Afrikaner republics. However, the war ended too soon for him. So, having come into a small inheritance, he decided to become a physician instead. Accumulating honors and prizes along the way, he succeeded and became a fellow of the Royal College of Surgeons of England in 1909.
His mentor was Sir Almroth Wright. Fleming assisted him at St. Mary’s Hospital in Paddington, and they were at the forefront of the burgeoning field of bacteriology. They were, for example, among the first to treat syphilis with the newly discovered Salvarsan, and they championed immunization through vaccination. With the outbreak of World War I, Fleming followed Wright into the Royal Army Medical Corps, conducting research on battlefield wounds at a laboratory near Boulogne. The infections Fleming inspected horrified him. After the war, again at St. Mary’s Hospital, he dedicated himself to finding anti-bacterial agents.
He succeed twice: “lysozyme” in 1921 and penicillin in 1928. To his great disappointment, he was unable to produce pure, potent concentrations of the drug. That had to await the work of Ernst Chain and Howard Florey in 1940. Meanwhile, Fleming studied the antibacterial properties of sulfa drugs. He was overjoyed that Chain and Florey succeeded where he had failed and that penicillin saved lives during World War II and afterward, but he was taken aback when with them he began to receive a stream of tributes, awards, decorations, honorary degrees, and fellowships, including the Nobel Prize in Physiology or Medicine in 1945. He was by nature a reserved man.
However, he adjusted to his role as one of the most lionized medical researchers of his generation and continued his work, both as a professor of medicine at the University of London from 1928 until 1948 and as director of the same St. Mary’s Hospital laboratory where he had started his career (renamed the Wright-Fleming Institute in 1948). He died soon after he retired in 1955.
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 of World War 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 inhuman history.
See also Antibacterial drugs; Artificial hormone; Genetically engineered insulin; Polio vaccine (Sabin); Polio vaccine (Salk); Reser-pine; Salvarsan; Tuberculosis vaccine; Typhus vaccine; Yellow fever vaccine.

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