Course: Scientific Discovery Instructor: Dr. Alexandra Vankley Presentation By: Sri Ram 10/21/03

Course: Scientific DiscoveryCourse: Scientific DiscoveryInstructor: Dr. Alexandra VankleyInstructor: Dr. Alexandra VankleyPresentation By: Sri Ram Presentation By: Sri Ram 10/21/0310/21/03

STORY OF PENCILLIN STORY OF PENCILLIN

Interesting FactsInteresting Facts

The wonder drugThe wonder drug The first antibiotic popularly knownThe first antibiotic popularly known The first antibiotic produced and used on a The first antibiotic produced and used on a

massive scalemassive scale The pioneer of chemotherapy The pioneer of chemotherapy

The 2 parts of the storyThe 2 parts of the story

a-the discovery of penicillin as an a-the discovery of penicillin as an antibacterial and Alexander Flemingantibacterial and Alexander Fleming

b-the discovery and realization of its b-the discovery and realization of its chemotherapeutic potential chemotherapeutic potential

Discovery of PenicillinDiscovery of Penicillin

BackgroundBackground

Works of Louis Pasteur and Robert Koch, Works of Louis Pasteur and Robert Koch, helped elucidate the connection between helped elucidate the connection between infectious diseases and the invasion of the infectious diseases and the invasion of the body by bacteria and other micro-body by bacteria and other micro-organisms . organisms .

Microbial DiscoveriesMicrobial Discoveries

YearYear Microbe Microbe discovereddiscovered

1880-821880-82 TyphoidTyphoid

18831883 CholeraCholera

18841884 TetanusTetanus

18861886 PneumoniaPneumonia

18941894 PlaguePlague

Related EventsRelated Events

In 1871, Joseph Lister ( antiseptic practice In 1871, Joseph Lister ( antiseptic practice surgery) - a mold in a sample of urine - inhibiting surgery) - a mold in a sample of urine - inhibiting bacterial growth. bacterial growth.

In 1875 John Tyndall - a species of In 1875 John Tyndall - a species of PenicilliumPenicillium caused some of his bacteria to burst.caused some of his bacteria to burst.

In 1877 Louis Pasteur and Jules Joubert -In 1877 Louis Pasteur and Jules Joubert -airborne microorganisms could inhibit the growth airborne microorganisms could inhibit the growth of anthrax bacilli . of anthrax bacilli .

Related Events contd.Related Events contd.

Ernest Duchesne in 1897 focused on the Ernest Duchesne in 1897 focused on the interaction betweeninteraction between E. coli E. coli and and Penicillium Penicillium glaucumglaucum . .

Inoculating mold and typhoid bacilli -prevented Inoculating mold and typhoid bacilli -prevented contraction of typhoid in animals. But, he died of contraction of typhoid in animals. But, he died of T.B before he could complete his research.T.B before he could complete his research.

Experiments carried out by Emmerich and Loew Experiments carried out by Emmerich and Loew (1899) and later by Gratia and Dath and others (1899) and later by Gratia and Dath and others did not give any favorable results.did not give any favorable results.

Related Events contd.Related Events contd.

Instead various forms of vaccination and Instead various forms of vaccination and serum treatment were evolved.serum treatment were evolved.

The first Nobel Prize for Physiology or The first Nobel Prize for Physiology or Medicine in 1901 was given for serum Medicine in 1901 was given for serum therapy for diphtheria. therapy for diphtheria.

Human and animal bodies - produce Human and animal bodies - produce protective substances in the fight against protective substances in the fight against the invaders.the invaders.

Sir Alexander FlemingSir Alexander Fleming


Born on August 6Born on August 6thth,1881 at Lochfield, ,1881 at Lochfield, Scotland in a farmer’s family .Scotland in a farmer’s family .

He had his early days spent more in the He had his early days spent more in the farms but was sound in his fundamental farms but was sound in his fundamental education.education.

1895-The untimely death of his father and 1895-The untimely death of his father and the success of the medical practice of his the success of the medical practice of his step-brother Tom had him relocated to step-brother Tom had him relocated to London.London.


1895 –He attended the Polytechnic School 1895 –He attended the Polytechnic School in Regent Street .in Regent Street .

1896-1900- He worked as a clerk in a 1896-1900- He worked as a clerk in a shipping firm.shipping firm.

1900- In 1900, when the Boer War broke 1900- In 1900, when the Boer War broke out joined the Scottish regiment but out joined the Scottish regiment but never saw the combat.never saw the combat.


Later encouraged by his brother and Later encouraged by his brother and supported by the money he received from supported by the money he received from an Uncle’s demise he looked towards a an Uncle’s demise he looked towards a medical career. medical career.

1901-He won a scholarship to St. Mary's 1901-He won a scholarship to St. Mary's Hospital Medical School, London Hospital Medical School, London University, Paddington and joined it. University, Paddington and joined it.

He qualified with distinction and received He qualified with distinction and received his degree in 1906his degree in 1906


His switch to bacteriology was even more His switch to bacteriology was even more surprising: if he took a position as a surgeon, he surprising: if he took a position as a surgeon, he would have to leave St. Mary's.would have to leave St. Mary's.

The captain of St. Mary's rifle club knew that and The captain of St. Mary's rifle club knew that and was desperate to improve his team. Knowing was desperate to improve his team. Knowing that Fleming was a great shot he did all he could that Fleming was a great shot he did all he could to keep him at St. Mary's.to keep him at St. Mary's.

He worked in the Inoculation Service and he He worked in the Inoculation Service and he convinced Fleming to join his department in convinced Fleming to join his department in order to work with its brilliant director -- and to order to work with its brilliant director -- and to join the rifle club.join the rifle club.

Sir Alexander FlemingSir Alexander Fleming 1906- Fleming joined the Inoculation Department as

medical bacteriologist under the direction of Sir Almroth Wright.

He made the St. Mary's Hospital Medical School his professional home for the rest of his life.

1914-Flemming became a lecturer at St.Mary’s.

1914-1918- Served as Captain in W W 1


1918 -He returned to St.Mary's.1918 -He returned to St.Mary's. 1928- He was elected Professor of the 1928- He was elected Professor of the

School in 1928 School in 1928 1943-He was elected Fellow of Royal 1943-He was elected Fellow of Royal

Society.Society. 1944-Flemming was knighted.1944-Flemming was knighted. 1945-Received his Nobel Prize.1945-Received his Nobel Prize.

1948-Elected the Emeritus Professor of 1948-Elected the Emeritus Professor of Bacteriology, University of London.Bacteriology, University of London.

1951-54-He was Rector of Edinburgh 1951-54-He was Rector of Edinburgh University.University.

Died on March 11Died on March 11thth,1955,1955

Fleming’s IdeologyFleming’s Ideology

Wright believed, as did Fleming, there Wright believed, as did Fleming, there were substances in the human body that were substances in the human body that could be used to fight infection, and could be used to fight infection, and strengthening the immune system was strengthening the immune system was key. key.

Hence, they believed more on vaccine Hence, they believed more on vaccine therapy rather than chemotherapy.therapy rather than chemotherapy.

Ehrlich’s “Salvarsan”Ehrlich’s “Salvarsan”

In 1909 German chemist-physician Paul Ehrlich In 1909 German chemist-physician Paul Ehrlich developed a chemical treatment for syphilis. developed a chemical treatment for syphilis.

salvarsan - "that which saves by arsenic". salvarsan - "that which saves by arsenic". Ehrlich’s samples were given to Fleming by Ehrlich’s samples were given to Fleming by

Wright and became efficient in its administration.Wright and became efficient in its administration. He did so with the new and difficult technique of He did so with the new and difficult technique of

intravenous injection. He soon developed such a intravenous injection. He soon developed such a busy practice he got the nickname "Private 606.“busy practice he got the nickname "Private 606.“

Antiseptics of that periodAntiseptics of that period

During World War I- wound-research During World War I- wound-research laboratory in Boulogne, France.laboratory in Boulogne, France.

Chemical antiseptics like carbolic acid Chemical antiseptics like carbolic acid (phenol) do not sterilize jagged wounds; (phenol) do not sterilize jagged wounds; rather, pus has its own antibacterial powers. rather, pus has its own antibacterial powers.

He was able to show that chemical He was able to show that chemical antiseptics in dilutions harmless to bacteria antiseptics in dilutions harmless to bacteria actually damage white blood corpuscles actually damage white blood corpuscles (leukocytes)—the body's first line of defense.(leukocytes)—the body's first line of defense.

Lysozyme DiscoveryLysozyme Discovery

Fleming looked for -a chemical like salvarsan, Fleming looked for -a chemical like salvarsan, that could help fight microbe infections.that could help fight microbe infections.

After war in 1920, back in St.Mary’s Fleming After war in 1920, back in St.Mary’s Fleming searched for an affective antiseptic.searched for an affective antiseptic.

He discovered Lysozyme, in nasal mucus . Its He discovered Lysozyme, in nasal mucus . Its an enzyme found in many body fluid, like tears, an enzyme found in many body fluid, like tears, etc. It is a natural antibacterial not effective etc. It is a natural antibacterial not effective against the stronger infectious agents.against the stronger infectious agents.

Lysozyme’s ActivityLysozyme’s Activity

LysozymeLysozyme

Lysozyme, in its natural state, seemed to Lysozyme, in its natural state, seemed to be more effective against harmless be more effective against harmless airborne bacteria than against disease-airborne bacteria than against disease-causing bacteria.causing bacteria.

And attempts to concentrate it, proved And attempts to concentrate it, proved unsuccessful.unsuccessful.

Fleming continued his research of finding Fleming continued his research of finding a better and less toxic antiseptic and a better and less toxic antiseptic and antibacterial. antibacterial.

The Chanced DiscoveryThe Chanced Discovery

Fleming's legendary discovery of penicillin Fleming's legendary discovery of penicillin occurred in 1928, while he was occurred in 1928, while he was investigating staphylococcus, a common investigating staphylococcus, a common bacteria then caused diseases ranging bacteria then caused diseases ranging from boils to disastrous infections.from boils to disastrous infections.

Fleming at his usual workFleming at his usual work

The Halo of PencillinThe Halo of Pencillin

He left a culture plate smeared with He left a culture plate smeared with Staphylococcus bacteria on his lab Staphylococcus bacteria on his lab bench while he went on a two-week bench while he went on a two-week holiday. holiday.

When he returned, he noticed a clear When he returned, he noticed a clear halo surrounding the yellow-green halo surrounding the yellow-green growth of a mold that had accidentally growth of a mold that had accidentally contaminated the plate. contaminated the plate.

The Halo of PencillinThe Halo of Pencillin

The culture-plateThe culture-plate

How This HappenedHow This Happened

Luckily, Fleming had not stored his Luckily, Fleming had not stored his culture in a warm incubator. London culture in a warm incubator. London was then hit by a cold spell, giving the was then hit by a cold spell, giving the mold a chance to grow.mold a chance to grow.

Later, as the temperature rose, the Later, as the temperature rose, the Staphylococcus bacteria grew, Staphylococcus bacteria grew, covering the entire plate--except for the covering the entire plate--except for the area surrounding the moldy area surrounding the moldy contaminant. contaminant.

Fleming’s DeductionFleming’s Deduction

Fleming correctly deduced -mold must Fleming correctly deduced -mold must have released a substance - inhibited have released a substance - inhibited the growth of the bacteria.the growth of the bacteria.

He was never clear on his He was never clear on his observations. The evidence of the first observations. The evidence of the first culture, which he photographed culture, which he photographed indicated that Fleming observed lysis, indicated that Fleming observed lysis, the weakening and destruction of the weakening and destruction of bacteria—as in his lysozyme studies. bacteria—as in his lysozyme studies.

Penicillin and Lysozyme ActivityPenicillin and Lysozyme Activity

Fleming’s DeductionFleming’s Deduction

But sometimes Fleming described it But sometimes Fleming described it inhibition, or prevention of bacterial -inhibition, or prevention of bacterial -evidenced by a clear zone surrounding evidenced by a clear zone surrounding the mold. the mold.

Although these two effects occur under Although these two effects occur under quite different conditions, Fleming quite different conditions, Fleming probably forgot which observation probably forgot which observation came first.came first.

Penicillin IdentifiedPenicillin Identified

He discovered that the antibacterial He discovered that the antibacterial substance was not produced by all molds, substance was not produced by all molds, only by strain of only by strain of Penicillium notatumPenicillium notatum).).

Although he could not isolate it, he named Although he could not isolate it, he named the active substance “penicillin.” the active substance “penicillin.”

He studied methods of producing the impure He studied methods of producing the impure product and determined its stability at product and determined its stability at different temperatures and over various different temperatures and over various lengths of time. lengths of time.

Penicillin is Non-ToxicPenicillin is Non-Toxic

Fleming found that penicillin was not toxic Fleming found that penicillin was not toxic to animals and that it did not harm white to animals and that it did not harm white blood cells (leucocytes) by injecting blood cells (leucocytes) by injecting healthy mice extract from the mold growth.healthy mice extract from the mold growth.

Previous, observations of such injections Previous, observations of such injections proved toxic and penicillin was an proved toxic and penicillin was an exception.exception.

Penicillin PropertiesPenicillin Properties

Penicillin would not be absorbed if Penicillin would not be absorbed if taken orally. taken orally.

Penicillin taken by injection - excreted Penicillin taken by injection - excreted in the urine in a matter of hours-well in the urine in a matter of hours-well before it could have its effects.before it could have its effects.

Moreover, the unstable penicillin was Moreover, the unstable penicillin was never available for clinical testing.never available for clinical testing.

Fleming’s ways of using PenicillinFleming’s ways of using Penicillin

For Fleming, penicillin's therapeutic For Fleming, penicillin's therapeutic potential - topical antisepsis. potential - topical antisepsis.

Fleming did continue to use in Fleming did continue to use in bacteriology. Penicillin suppressed the bacteriology. Penicillin suppressed the growth of certain bacterial species, growth of certain bacterial species, allowing one to selectively culture allowing one to selectively culture certain others (such as those causing certain others (such as those causing influenza, acne and whooping cough).influenza, acne and whooping cough).

Selective InhibitionSelective Inhibition

Penicillin in vaccine productionPenicillin in vaccine production

Penicillin became a valuable in Penicillin became a valuable in manufacture of vaccines. manufacture of vaccines.

The penicillin was crude--good enough The penicillin was crude--good enough for Fleming's purpose, but hardly for Fleming's purpose, but hardly strong enough to destroy a serious strong enough to destroy a serious human infection. human infection.

Paper on PenicillinPaper on Penicillin

Little notice was taken by the scientific Little notice was taken by the scientific community of his paper published in community of his paper published in the the British Journal of Experimental British Journal of Experimental PathologyPathology (June 1929). (June 1929).

Explanation for Failure Explanation for Failure

His belief - cure comes from within the His belief - cure comes from within the body itself rather than from an external body itself rather than from an external chemical agent. chemical agent.

Difficulties -he had experienced in Difficulties -he had experienced in isolating and stabilizing penicillin, isolating and stabilizing penicillin, producing sufficient quantities for producing sufficient quantities for clinical trials- prevented him from clinical trials- prevented him from realizing the full fruits of his research.realizing the full fruits of his research.

Fleming-After PenicillinFleming-After Penicillin

Fleming had turned his research to other Fleming had turned his research to other chemical antibacterials, the sulphonamides chemical antibacterials, the sulphonamides

He kept producing and supplying his sample He kept producing and supplying his sample of penicillin to other labs and researchers for of penicillin to other labs and researchers for various studies and experiments.various studies and experiments.

For more than a decade or so no progress For more than a decade or so no progress was made in the discovery of penicillin.was made in the discovery of penicillin.

End of the 1End of the 1stst half half

The 2The 2ndnd half half

The discovery and realization of the The discovery and realization of the chemotherapeutic potential of Penicillinchemotherapeutic potential of Penicillin

Sir Howard Walter FloreySir Howard Walter Florey


Born on September 24, 1898, at Born on September 24, 1898, at Adelaide, South Australia .Adelaide, South Australia .

He graduated in M.B., B.S. in 1921from He graduated in M.B., B.S. in 1921from Adelaide University. Adelaide University.

He was awarded a Rhodes Scholarship He was awarded a Rhodes Scholarship to Magdalene College, Oxford, leading to Magdalene College, Oxford, leading to the degrees of B.Sc. and M.A. (1924). to the degrees of B.Sc. and M.A. (1924).


In 1925 he visited the United States on a In 1925 he visited the United States on a Rockefeller Travelling Fellowship for a year,Rockefeller Travelling Fellowship for a year,

Returned in 1926 to a Fellowship at Gonville Returned in 1926 to a Fellowship at Gonville and Caius College, Cambridge, received his and Caius College, Cambridge, received his Ph.D. in 1927.Ph.D. in 1927.

In 1931 he succeeded to the Joseph Hunter In 1931 he succeeded to the Joseph Hunter Chair of Pathology at the University of Chair of Pathology at the University of Sheffield. Sheffield.


Leaving Sheffield in 1935 he became Leaving Sheffield in 1935 he became Professor of Pathology and a Fellow of Professor of Pathology and a Fellow of Lincoln College, Oxford. Lincoln College, Oxford.

1936-He was made Director to the Sir 1936-He was made Director to the Sir William Dunn School of Pathology.William Dunn School of Pathology.

He was made an Honorary Fellow of He was made an Honorary Fellow of Gonville and Caius College, Cambridge Gonville and Caius College, Cambridge in 1946 in 1946


Honorary Fellow of Magdalen College, Honorary Fellow of Magdalen College, Oxford in 1952.Oxford in 1952.

In 1962 he was made Provost of The In 1962 he was made Provost of The Queen's College, Oxford Queen's College, Oxford

In 1944 he was created a Knight In 1944 he was created a Knight Bachelor. Bachelor.

In 1945 was awarded the Nobel Prize.In 1945 was awarded the Nobel Prize. Dr. Florey died in 1968.Dr. Florey died in 1968.

Ernst Boris ChainErnst Boris Chain


Born on June 19, 1906, in Berlin.Born on June 19, 1906, in Berlin. He next attended the Friedrich-Wilhelm He next attended the Friedrich-Wilhelm

University, Berlin, where he graduated in University, Berlin, where he graduated in chemistry in 1930. chemistry in 1930.

He worked for three years at the Charité He worked for three years at the Charité Hospital, Berlin, on enzyme research. Hospital, Berlin, on enzyme research.

In 1933, after the access to power of the Nazi In 1933, after the access to power of the Nazi regime in Germany, he emigrated to England. regime in Germany, he emigrated to England.


He first worked on phospholipids at the He first worked on phospholipids at the School of Biochemistry, Cambridge, under School of Biochemistry, Cambridge, under the direction of Sir Frederick Gowland the direction of Sir Frederick Gowland Hopkins .Hopkins .

In 1935 he was invited to Oxford University In 1935 he was invited to Oxford University where he worked in the Sir William Dunn where he worked in the Sir William Dunn School of Pathology.School of Pathology.

in 1936, he was made demonstrator and in 1936, he was made demonstrator and lecturer in chemical pathology. lecturer in chemical pathology.


In 1948 he was appointed Scientific In 1948 he was appointed Scientific Director of the International Research Director of the International Research Centre for Chemical Microbiology at the Centre for Chemical Microbiology at the Istituto Superiore di Sanita, Rome. Istituto Superiore di Sanita, Rome.

He became Professor of Biochemistry He became Professor of Biochemistry at Imperial College, University of at Imperial College, University of London, in 1961London, in 1961

1945-Awarded Nobel prize1945-Awarded Nobel prize Dr.Chain died in 1979Dr.Chain died in 1979

Florey’s TeamFlorey’s Team

Florey recruited -a interdisciplinary Florey recruited -a interdisciplinary group of scientists- to study group of scientists- to study pathological evidence of disease and pathological evidence of disease and physiological processes by which physiological processes by which those symptoms arose, traced to the those symptoms arose, traced to the chemical and even the molecular levelchemical and even the molecular level..

Florey joined by ChainFlorey joined by Chain

Among his first hires was the Among his first hires was the biochemist Ernst Boris Chain.biochemist Ernst Boris Chain.

With Chain , one of the projects With Chain , one of the projects pursued was the crystallization of pursued was the crystallization of lysozyme and the characterization of its lysozyme and the characterization of its substrate—the location on bacteria to substrate—the location on bacteria to which it usually attaches.which it usually attaches.

Future PlansFuture Plans

In 1938, while the lysozyme research In 1938, while the lysozyme research was concluding, Florey and Chain was concluding, Florey and Chain decided to study selected antibacterial decided to study selected antibacterial substances produced by certain substances produced by certain microorganisms. They thought these microorganisms. They thought these substances were all enzymes like substances were all enzymes like lysozyme.lysozyme.

Chain’s suggestionChain’s suggestion

This process was greatly facilitated by This process was greatly facilitated by Chain's near-photographic recall of the Chain's near-photographic recall of the many scientific papers he had read, many scientific papers he had read, including Fleming's 1929 paper on including Fleming's 1929 paper on penicillin. penicillin.

Work on Penicillin BeginsWork on Penicillin Begins

They originally chose substances from They originally chose substances from three organisms: pyocyanase, a topical three organisms: pyocyanase, a topical antibacterial, from antibacterial, from Bacillus Bacillus pyocyaneuspyocyaneus; extracts from certain ; extracts from certain organisms in the soil called organisms in the soil called actinomycetes; and penicillinactinomycetes; and penicillin

Work on PenicillinWork on Penicillin

While Florey and Chain were While Florey and Chain were assembling grants and funds, work was assembling grants and funds, work was begun on penicillin.begun on penicillin.

Fortuitously, there was already a Fortuitously, there was already a penicillin culture at the William Dunn penicillin culture at the William Dunn SchoolSchool

The research program rapidly narrowed The research program rapidly narrowed its focus to penicillin alone. its focus to penicillin alone.

Isolating Pure PenicillinIsolating Pure Penicillin

Chain, along with another chemist, Chain, along with another chemist, E.P.Abraham -technique for purifying E.P.Abraham -technique for purifying and concentrating penicillin. and concentrating penicillin.

The key- pH of the “juice,” the The key- pH of the “juice,” the sample's temperature, freeze-drying it. sample's temperature, freeze-drying it.

Later improved on by Norman Heatley Later improved on by Norman Heatley and other scientists.and other scientists.

Purification DifficultyPurification Difficulty

Gallons and gallons of mold broth were Gallons and gallons of mold broth were used to produce an amount just large used to produce an amount just large enough to cover a fingernail!enough to cover a fingernail!

First Toxicity TestFirst Toxicity Test

In March 1940 Chain injected mice with In March 1940 Chain injected mice with a sample of the penicillin extracted.a sample of the penicillin extracted.

Far higher dosage than Fleming's - the Far higher dosage than Fleming's - the mice survived apparently unharmed.mice survived apparently unharmed.

The more-concentrated penicillin had The more-concentrated penicillin had passed its first toxicity test. passed its first toxicity test.

Florey ImpressedFlorey Impressed

Florey directed that the antibacterial Florey directed that the antibacterial properties of penicillin in mice be properties of penicillin in mice be tested—the step that Fleming had not tested—the step that Fleming had not taken.taken.

Heatley’s ContributionsHeatley’s Contributions

Norman Heatley -technical inventions Norman Heatley -technical inventions to produce penicillin on a larger scale. to produce penicillin on a larger scale.

Heatley- contributed a lot to the Heatley- contributed a lot to the purification process and different purification process and different methods of growing mould in various methods of growing mould in various containers. containers.

First Therapeutic TestFirst Therapeutic Test

In May 1940, the team had been able to In May 1940, the team had been able to produce enough penicillin to test on produce enough penicillin to test on infected animals . infected animals .

Eight mice were infected with a deadly Eight mice were infected with a deadly dose of streptococci bacteria each. One dose of streptococci bacteria each. One hour later, four of them were injected hour later, four of them were injected with penicillin and four mice were left with penicillin and four mice were left without treatment.without treatment.

First Therapeutic TestFirst Therapeutic Test

with Penicillin without Penicillin

Mice Injected with Bacteria

The MiracleThe Miracle

The four mice that hadn't been injected The four mice that hadn't been injected with penicillin started to show signs of with penicillin started to show signs of illness and later died.illness and later died.

The four mice treated with penicillin The four mice treated with penicillin remained fine!remained fine!

Hearing this Howard Florey exclaimed, Hearing this Howard Florey exclaimed, "It looks like a miracle!""It looks like a miracle!"

The MiracleThe Miracle

The Mice injected with Penicillin survive !

PublicationPublication

On 24 August 1940 Florey and Chain On 24 August 1940 Florey and Chain reported their findings in the reported their findings in the LancetLancet; ;

By then World War II had already By then World War II had already engulfed Europe, calling for finding engulfed Europe, calling for finding means of combating the diseases and means of combating the diseases and infections of war to hold the advantage.infections of war to hold the advantage.

The First Trial on HumansThe First Trial on Humans

The first patient was a young woman The first patient was a young woman volunteer with non-treatable cancer (January volunteer with non-treatable cancer (January 1941) . 1941) .

She showed an alarming reaction—trembling She showed an alarming reaction—trembling and sharply rising fever.and sharply rising fever.

With paper chromatography- Abraham was With paper chromatography- Abraham was able to separate out the impurities -showed able to separate out the impurities -showed that they caused the adverse reaction.that they caused the adverse reaction.

The First Clinical TrialThe First Clinical Trial

On 12 February 1941 a policeman with On 12 February 1941 a policeman with an invasive infection - first patient with an invasive infection - first patient with an infection to be treated with an infection to be treated with penicillin. penicillin.

The dosages and the length of The dosages and the length of treatment required were being worked treatment required were being worked out by just trials.out by just trials.

The First Clinical TrialThe First Clinical Trial

First improved and then relapsed. First improved and then relapsed. The penicillin supply ran out- even The penicillin supply ran out- even

retrieving penicillin from the man's own retrieving penicillin from the man's own urine- failed to save him.urine- failed to save him.

Florey vowed that from then on he Florey vowed that from then on he would always have enough penicillin to would always have enough penicillin to complete a treatment.complete a treatment.

Efforts to Mass ProduceEfforts to Mass Produce

Increasing production - overriding Increasing production - overriding importance. importance.

PenicilliumPenicillium mold requires air to grow- mold requires air to grow- surface-cultured in regular laboratory surface-cultured in regular laboratory flasks. All manner of vessels used- flasks. All manner of vessels used- hospital bedpans, made-to-order hospital bedpans, made-to-order ceramic pots,etc ceramic pots,etc

Industrial ProductionIndustrial Production

Florey approached various British Florey approached various British pharmaceutical firms.pharmaceutical firms.

British pharmaceutical firms-committed British pharmaceutical firms-committed to manufacturing other drugs needed to manufacturing other drugs needed for military and civilian populations-for military and civilian populations-devastated by enemy bombardment. devastated by enemy bombardment.

Entry of USA Entry of USA

To obtain the assistance of the United To obtain the assistance of the United States- noncombatant- in increasing States- noncombatant- in increasing production and furthering research, production and furthering research, Florey and Heatley flew across the Florey and Heatley flew across the Atlantic in the beginning of July 1941. Atlantic in the beginning of July 1941.

Joint ActionJoint Action

Florey’s contacts helped him get to Florey’s contacts helped him get to have the production taken up by the have the production taken up by the U.S Firms and Government agencies. U.S Firms and Government agencies.

Soon it was decided to have an Soon it was decided to have an expedite unified action on penicillin .expedite unified action on penicillin .

Joint ActionJoint Action

At the height of the program- the At the height of the program- the British-American penicillin effort-British-American penicillin effort-thousands of people and some thirty-thousands of people and some thirty-five institutions: university chemistry five institutions: university chemistry and physics departments, government and physics departments, government agencies, research foundations, and agencies, research foundations, and pharmaceutical companies.pharmaceutical companies.

Only Life Saver in WarOnly Life Saver in War

By D-day there was enough penicillin By D-day there was enough penicillin on hand to treat every soldier who on hand to treat every soldier who needed it. By the end of World War II, it needed it. By the end of World War II, it had saved millions of lives. had saved millions of lives.

Efforts to Study Penicillin Efforts to Study Penicillin

Some chemists -synthesize penicillin Some chemists -synthesize penicillin from a few organic chemicals. from a few organic chemicals.

Efforts to understand the molecular Efforts to understand the molecular structure of the penicillin. structure of the penicillin.

Reacting the substance with various Reacting the substance with various chemical reagents, which resulted in chemical reagents, which resulted in products of known structure. products of known structure.

Efforts to Study PenicillinEfforts to Study Penicillin

From these bits of structural From these bits of structural information -deduce how the original information -deduce how the original molecule was organized.molecule was organized.

At Oxford the problem of determining At Oxford the problem of determining penicillin's structure was given to penicillin's structure was given to Chain, Abraham, and Robert Robinson, Chain, Abraham, and Robert Robinson, a senior organic chemist .a senior organic chemist .

Penicillin StructurePenicillin Structure

By fall 1943, groups working at Oxford By fall 1943, groups working at Oxford and at Merck had proposed two and at Merck had proposed two different structures penicillin molecule. different structures penicillin molecule.

Chain and Abraham as well as by Chain and Abraham as well as by Robert Burns Woodward at Harvard— Robert Burns Woodward at Harvard— four-membered beta- lactam ring lay at four-membered beta- lactam ring lay at the heart of the penicillin molecule the heart of the penicillin molecule

Robinson instead proposed a structure Robinson instead proposed a structure based on oxazalone based on oxazalone

Proposed StructuresProposed Structures

Beta-lactam ring structure forpenicillin. The beta-lactam ringis shown in red.

Proposed oxazalone structure forpenicillin. The oxazalone ringis shown in red.

Newer Techniques to StudyNewer Techniques to Study

New techniques for analyzing the New techniques for analyzing the structure of organic molecules - X-ray structure of organic molecules - X-ray crystallography- practiced by Dorothy crystallography- practiced by Dorothy Hodgkin Hodgkin

In 1945 she was able confirmed Chain In 1945 she was able confirmed Chain and Abraham's deduction. This and Abraham's deduction. This evidence ran counter to Robinson's evidence ran counter to Robinson's proposed structure for penicillin.proposed structure for penicillin.

Production by Fermentation onlyProduction by Fermentation only

In 1957 John Sheehan created such a In 1957 John Sheehan created such a synthesis, but fermentation - the synthesis, but fermentation - the commercial production of penicillin and commercial production of penicillin and related antibiotics. related antibiotics.

But the structural knowledge gained - But the structural knowledge gained - developing penicillin-like antibiotics developing penicillin-like antibiotics that were more effective, convenient to that were more effective, convenient to give and had fewer side effects. give and had fewer side effects.

Awards timeAwards time

World War II ended and the Nobel World War II ended and the Nobel Prizes in physiology or medicine Prizes in physiology or medicine distributed to Fleming, Florey, and distributed to Fleming, Florey, and Chain for their work on penicillin.Chain for their work on penicillin.

The Nobel Prize in Physiology or Medicine 1945The Nobel Prize in Physiology or Medicine 1945

"for the discovery of penicillin and its curative effect in various infectious diseases""for the discovery of penicillin and its curative effect in various infectious diseases"

Penicillin-The master DrugPenicillin-The master Drug

Pneumonia, syphilis, gonorrhea, Pneumonia, syphilis, gonorrhea, diphtheria, scarlet fever and many diphtheria, scarlet fever and many wound and childbirth infections that wound and childbirth infections that once killed indiscriminately suddenly once killed indiscriminately suddenly became treatable.became treatable.

Deaths caused by bacterial infections Deaths caused by bacterial infections plummetedplummeted

Words of Caution Words of Caution

By this time, even Fleming was aware By this time, even Fleming was aware that penicillin had an Achilles' heel. that penicillin had an Achilles' heel.

He wrote in 1946 that "the He wrote in 1946 that "the administration of too small doses ... administration of too small doses ... leads to the production of resistant leads to the production of resistant strains of bacteria." It's a problem that strains of bacteria." It's a problem that plagues us to this day. plagues us to this day.

ReferencesReferences

www.nobel.sewww.nobel.se www.chemheritage.comwww.chemheritage.com www.hisortylearningsite.co.ukwww.hisortylearningsite.co.uk www.pbs.orgwww.pbs.org www.time.comwww.time.com

Course: Scientific Discovery Instructor: Dr. Alexandra Vankley Presentation By: Sri Ram 10/21/03

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