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Course: Scientific Discovery

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Title: Course: Scientific Discovery


1
  • Course Scientific Discovery
  • Instructor Dr. Alexandra Vankley
  • Presentation By Sri Ram
  • 10/21/03

2
STORY OF PENCILLIN
3
Interesting Facts
  • The wonder drug
  • The first antibiotic popularly known
  • The first antibiotic produced and used on a
    massive scale
  • The pioneer of chemotherapy

4
The 2 parts of the story
  • a-the discovery of penicillin as an antibacterial
    and Alexander Fleming
  • b-the discovery and realization of its
    chemotherapeutic potential

5
Discovery of Penicillin
6
Background
  • Works of Louis Pasteur and Robert Koch, helped
    elucidate the connection between infectious
    diseases and the invasion of the body by bacteria
    and other micro-organisms .

7
Microbial Discoveries
Year Microbe discovered
1880-82 Typhoid
1883 Cholera
1884 Tetanus
1886 Pneumonia
1894 Plague
8
Related Events
  • In 1871, Joseph Lister ( antiseptic practice
    surgery) - a mold in a sample of urine -
    inhibiting bacterial growth.
  • In 1875 John Tyndall - a species of Penicillium
    caused some of his bacteria to burst.
  • In 1877 Louis Pasteur and Jules Joubert
    -airborne microorganisms could inhibit the growth
    of anthrax bacilli .

9
Related Events contd.
  • Ernest Duchesne in 1897 focused on the
    interaction between E. coli and Penicillium
    glaucum .
  • Inoculating mold and typhoid bacilli -prevented
    contraction of typhoid in animals. But, he died
    of T.B before he could complete his research.
  • Experiments carried out by Emmerich and Loew
    (1899) and later by Gratia and Dath and others
    did not give any favorable results.

10
Related Events contd.
  • Instead various forms of vaccination and serum
    treatment were evolved.
  • The first Nobel Prize for Physiology or Medicine
    in 1901 was given for serum therapy for
    diphtheria.
  • Human and animal bodies - produce protective
    substances in the fight against the invaders.

11
Sir Alexander Fleming
12
Sir Alexander Fleming
  • Born on August 6th,1881 at Lochfield, Scotland in
    a farmers family .
  • He had his early days spent more in the farms but
    was sound in his fundamental education.
  • 1895-The untimely death of his father and the
    success of the medical practice of his
    step-brother Tom had him relocated to London.

13
Sir Alexander Fleming
  • 1895 He attended the Polytechnic School in
    Regent Street .
  • 1896-1900- He worked as a clerk in a shipping
    firm.
  • 1900- In 1900, when the Boer War broke out
    joined the Scottish regiment but never saw the
    combat.

14
Sir Alexander Fleming
  • Later encouraged by his brother and supported by
    the money he received from an Uncles demise he
    looked towards a medical career.
  • 1901-He won a scholarship to St. Mary's Hospital
    Medical School, London University, Paddington and
    joined it.
  • He qualified with distinction and received his
    degree in 1906

15
Sir Alexander Fleming
  • His switch to bacteriology was even more
    surprising if he took a position as a surgeon,
    he would have to leave St. Mary's.
  • The captain of St. Mary's rifle club knew that
    and was desperate to improve his team. Knowing
    that Fleming was a great shot he did all he could
    to keep him at St. Mary's.
  • He worked in the Inoculation Service and he
    convinced Fleming to join his department in order
    to work with its brilliant director -- and to
    join the rifle club.

16
Sir 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.Marys.
  • 1914-1918- Served as Captain in W W 1

1906 he joined the staff of the
17
Sir Alexander Fleming
  • 1918 -He returned to St.Mary's.
  • 1928- He was elected Professor of the School in
    1928
  • 1943-He was elected Fellow of Royal Society.
  • 1944-Flemming was knighted.
  • 1945-Received his Nobel Prize.

18
  • 1948-Elected the Emeritus Professor of
    Bacteriology, University of London.
  • 1951-54-He was Rector of Edinburgh University.
  • Died on March 11th,1955

19
Flemings Ideology
  • Wright believed, as did Fleming, there were
    substances in the human body that could be used
    to fight infection, and strengthening the immune
    system was key.
  • Hence, they believed more on vaccine therapy
    rather than chemotherapy.

20
Ehrlichs Salvarsan
  • In 1909 German chemist-physician Paul Ehrlich
    developed a chemical treatment for syphilis.
  • salvarsan - "that which saves by arsenic".
  • Ehrlichs samples were given to Fleming by Wright
    and became efficient in its administration.
  • He did so with the new and difficult technique
    of intravenous injection. He soon developed such
    a busy practice he got the nickname "Private
    606.

21
Antiseptics of that period
  • During World War I- wound-research laboratory in
    Boulogne, France.
  • Chemical antiseptics like carbolic acid (phenol)
    do not sterilize jagged wounds rather, pus has
    its own antibacterial powers.
  • He was able to show that chemical antiseptics in
    dilutions harmless to bacteria actually damage
    white blood corpuscles (leukocytes)the body's
    first line of defense.

22
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23
Lysozyme Discovery
  • Fleming looked for -a chemical like salvarsan,
    that could help fight microbe infections.
  • After war in 1920, back in St.Marys Fleming
    searched for an affective antiseptic.
  • He discovered Lysozyme, in nasal mucus . Its an
    enzyme found in many body fluid, like tears,
    etc. It is a natural antibacterial not effective
    against the stronger infectious agents.

24
Lysozymes Activity
25
Lysozyme
  • Lysozyme, in its natural state, seemed to be more
    effective against harmless airborne bacteria than
    against disease-causing bacteria.
  • And attempts to concentrate it, proved
    unsuccessful.
  • Fleming continued his research of finding a
    better and less toxic antiseptic and
    antibacterial.

26
The Chanced Discovery
  • Fleming's legendary discovery of penicillin
    occurred in 1928, while he was investigating
    staphylococcus, a common bacteria then caused
    diseases ranging from boils to disastrous
    infections.

27
Fleming at his usual work
28
The Halo of Pencillin
  • He left a culture plate smeared with
    Staphylococcus bacteria on his lab bench while he
    went on a two-week holiday.
  • When he returned, he noticed a clear halo
    surrounding the yellow-green growth of a mold
    that had accidentally contaminated the plate.

29
The Halo of Pencillin
30
The culture-plate
31
How This Happened
  • Luckily, Fleming had not stored his culture in
    a warm incubator. London was then hit by a cold
    spell, giving the mold a chance to grow.
  • Later, as the temperature rose, the
    Staphylococcus bacteria grew, covering the entire
    plate--except for the area surrounding the moldy
    contaminant.

32
Flemings Deduction
  • Fleming correctly deduced -mold must have
    released a substance - inhibited the growth of
    the bacteria.
  • He was never clear on his observations. The
    evidence of the first culture, which he
    photographed indicated that Fleming observed
    lysis, the weakening and destruction of
    bacteriaas in his lysozyme studies.

33
Penicillin and Lysozyme Activity
34
Flemings Deduction
  • But sometimes Fleming described it inhibition, or
    prevention of bacterial -evidenced by a clear
    zone surrounding the mold.
  • Although these two effects occur under quite
    different conditions, Fleming probably forgot
    which observation came first.

35
Penicillin Identified
  • He discovered that the antibacterial substance
    was not produced by all molds, only by strain of
    Penicillium notatum).
  • Although he could not isolate it, he named the
    active substance penicillin.
  • He studied methods of producing the impure
    product and determined its stability at different
    temperatures and over various lengths of time.

36
Penicillin is Non-Toxic
  • Fleming found that penicillin was not toxic to
    animals and that it did not harm white blood
    cells (leucocytes) by injecting healthy mice
    extract from the mold growth.
  • Previous, observations of such injections proved
    toxic and penicillin was an exception.

37
Penicillin Properties
  • Penicillin would not be absorbed if taken orally.
  • Penicillin taken by injection - excreted in the
    urine in a matter of hours-well before it could
    have its effects.
  • Moreover, the unstable penicillin was never
    available for clinical testing.

38
Flemings ways of using Penicillin
  • For Fleming, penicillin's therapeutic potential -
    topical antisepsis.
  • Fleming did continue to use in bacteriology.
    Penicillin suppressed the growth of certain
    bacterial species, allowing one to selectively
    culture certain others (such as those causing
    influenza, acne and whooping cough).

39
Selective Inhibition
40
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41
Penicillin in vaccine production
  • Penicillin became a valuable in manufacture of
    vaccines.
  • The penicillin was crude--good enough for
    Fleming's purpose, but hardly strong enough to
    destroy a serious human infection.

42
Paper on Penicillin
  • Little notice was taken by the scientific
    community of his paper published in the British
    Journal of Experimental Pathology (June 1929).

43
Explanation for Failure
  • His belief - cure comes from within the body
    itself rather than from an external chemical
    agent.
  • Difficulties -he had experienced in isolating and
    stabilizing penicillin, producing sufficient
    quantities for clinical trials- prevented him
    from realizing the full fruits of his research.

44
Fleming-After Penicillin
  • Fleming had turned his research to other chemical
    antibacterials, the sulphonamides
  • He kept producing and supplying his sample of
    penicillin to other labs and researchers for
    various studies and experiments.
  • For more than a decade or so no progress was made
    in the discovery of penicillin.

45
End of the 1st half
46
The 2nd half
  • The discovery and realization of the
    chemotherapeutic potential of Penicillin

47
Sir Howard Walter Florey
48
Sir Howard Walter Florey
  • Born on September 24, 1898, at Adelaide, South
    Australia .
  • He graduated in M.B., B.S. in 1921from Adelaide
    University.
  • He was awarded a Rhodes Scholarship to Magdalene
    College, Oxford, leading to the degrees of B.Sc.
    and M.A. (1924).

49
Sir Howard Walter Florey
  • In 1925 he visited the United States on a
    Rockefeller Travelling Fellowship for a year,
  • Returned in 1926 to a Fellowship at Gonville and
    Caius College, Cambridge, received his Ph.D. in
    1927.
  • In 1931 he succeeded to the Joseph Hunter Chair
    of Pathology at the University of Sheffield.

50
Sir Howard Walter Florey
  • Leaving Sheffield in 1935 he became Professor of
    Pathology and a Fellow of Lincoln College,
    Oxford.
  • 1936-He was made Director to the Sir William Dunn
    School of Pathology.
  • He was made an Honorary Fellow of Gonville and
    Caius College, Cambridge in 1946

51
Sir Howard Walter Florey
  • Honorary Fellow of Magdalen College, Oxford in
    1952.
  • In 1962 he was made Provost of The Queen's
    College, Oxford
  • In 1944 he was created a Knight Bachelor.
  • In 1945 was awarded the Nobel Prize.
  • Dr. Florey died in 1968.

52
Ernst Boris Chain
  •  

53
Ernst Boris Chain
  • Born on June 19, 1906, in Berlin.
  • He next attended the Friedrich-Wilhelm
    University, Berlin, where he graduated in
    chemistry in 1930.
  • He worked for three years at the Charité
    Hospital, Berlin, on enzyme research.
  • In 1933, after the access to power of the Nazi
    regime in Germany, he emigrated to England.

54
Ernst Boris Chain
  • He first worked on phospholipids at the School of
    Biochemistry, Cambridge, under the direction of
    Sir Frederick Gowland Hopkins .
  • In 1935 he was invited to Oxford University where
    he worked in the Sir William Dunn School of
    Pathology.
  • in 1936, he was made demonstrator and lecturer in
    chemical pathology.

55
Ernst Boris Chain
  • In 1948 he was appointed Scientific Director of
    the International Research Centre for Chemical
    Microbiology at the Istituto Superiore di Sanita,
    Rome.
  • He became Professor of Biochemistry at Imperial
    College, University of London, in 1961
  • 1945-Awarded Nobel prize
  • Dr.Chain died in 1979

56
Floreys Team
  • Florey recruited -a interdisciplinary group of
    scientists- to study pathological evidence of
    disease and physiological processes by which
    those symptoms arose, traced to the chemical and
    even the molecular level.

57
Florey joined by Chain
  • Among his first hires was the biochemist Ernst
    Boris Chain.
  • With Chain , one of the projects pursued was the
    crystallization of lysozyme and the
    characterization of its substratethe location on
    bacteria to which it usually attaches.

58
Future Plans
  • In 1938, while the lysozyme research was
    concluding, Florey and Chain decided to study
    selected antibacterial substances produced by
    certain microorganisms. They thought these
    substances were all enzymes like lysozyme.

59
Chains suggestion
  • This process was greatly facilitated by Chain's
    near-photographic recall of the many scientific
    papers he had read, including Fleming's 1929
    paper on penicillin.

60
Work on Penicillin Begins
  • They originally chose substances from three
    organisms pyocyanase, a topical antibacterial,
    from Bacillus pyocyaneus extracts from certain
    organisms in the soil called actinomycetes and
    penicillin

61
Work on Penicillin
  • While Florey and Chain were assembling grants and
    funds, work was begun on penicillin.
  • Fortuitously, there was already a penicillin
    culture at the William Dunn School
  • The research program rapidly narrowed its focus
    to penicillin alone.

62
Isolating Pure Penicillin
  • Chain, along with another chemist, E.P.Abraham
    -technique for purifying and concentrating
    penicillin.
  • The key- pH of the juice, the sample's
    temperature, freeze-drying it.
  • Later improved on by Norman Heatley and other
    scientists.

63
Purification Difficulty
  • Gallons and gallons of mold broth were used to
    produce an amount just large enough to cover a
    fingernail!

64
First Toxicity Test
  • In March 1940 Chain injected mice with a sample
    of the penicillin extracted.
  • Far higher dosage than Fleming's - the mice
    survived apparently unharmed.
  • The more-concentrated penicillin had passed its
    first toxicity test.

65
Florey Impressed
  • Florey directed that the antibacterial
    properties of penicillin in mice be testedthe
    step that Fleming had not taken.

66
Heatleys Contributions
  • Norman Heatley -technical inventions to produce
    penicillin on a larger scale.
  • Heatley- contributed a lot to the purification
    process and different methods of growing mould in
    various containers.

67
First Therapeutic Test
  • In May 1940, the team had been able to produce
    enough penicillin to test on infected animals .
  • Eight mice were infected with a deadly dose of
    streptococci bacteria each. One hour later, four
    of them were injected with penicillin and four
    mice were left without treatment.

68
First Therapeutic Test
Mice Injected with Bacteria

with Penicillin
without Penicillin
69
The Miracle
  • The four mice that hadn't been injected with
    penicillin started to show signs of illness and
    later died.
  • The four mice treated with penicillin remained
    fine!
  • Hearing this Howard Florey exclaimed, "It looks
    like a miracle!"

70
The Miracle
The Mice injected with Penicillin survive !
71
Publication
  • On 24 August 1940 Florey and Chain reported their
    findings in the Lancet
  • By then World War II had already engulfed Europe,
    calling for finding means of combating the
    diseases and infections of war to hold the
    advantage.

72
The First Trial on Humans
  • The first patient was a young woman volunteer
    with non-treatable cancer (January 1941) .
  • She showed an alarming reactiontrembling and
    sharply rising fever.
  • With paper chromatography- Abraham was able to
    separate out the impurities -showed that they
    caused the adverse reaction.

73
The First Clinical Trial
  • On 12 February 1941 a policeman with an invasive
    infection - first patient with an infection to be
    treated with penicillin.
  • The dosages and the length of treatment required
    were being worked out by just trials.

74
The First Clinical Trial
  • First improved and then relapsed.
  • The penicillin supply ran out- even retrieving
    penicillin from the man's own urine- failed to
    save him.
  • Florey vowed that from then on he would always
    have enough penicillin to complete a treatment.

75
Efforts to Mass Produce
  • Increasing production - overriding importance.
  • Penicillium mold requires air to grow-
    surface-cultured in regular laboratory flasks.
    All manner of vessels used- hospital bedpans,
    made-to-order ceramic pots,etc

76
Industrial Production
  • Florey approached various British pharmaceutical
    firms.
  • British pharmaceutical firms-committed to
    manufacturing other drugs needed for military and
    civilian populations-devastated by enemy
    bombardment.

77
Entry of USA
  • To obtain the assistance of the United States-
    noncombatant- in increasing production and
    furthering research, Florey and Heatley flew
    across the Atlantic in the beginning of July
    1941.

78
Joint Action
  • Floreys contacts helped him get to have the
    production taken up by the U.S Firms and
    Government agencies.
  • Soon it was decided to have an expedite unified
    action on penicillin .

79
Joint Action
  • At the height of the program- the
    British-American penicillin effort-thousands of
    people and some thirty-five institutions
    university chemistry and physics departments,
    government agencies, research foundations, and
    pharmaceutical companies.

80
Only Life Saver in War
  • By D-day there was enough penicillin on hand
    to treat every soldier who needed it. By the end
    of World War II, it had saved millions of lives.

81
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82
Efforts to Study Penicillin
  • Some chemists -synthesize penicillin from a few
    organic chemicals.
  • Efforts to understand the molecular structure of
    the penicillin.
  • Reacting the substance with various chemical
    reagents, which resulted in products of known
    structure.

83
Efforts to Study Penicillin
  • From these bits of structural information -deduce
    how the original molecule was organized.
  • At Oxford the problem of determining penicillin's
    structure was given to Chain, Abraham, and Robert
    Robinson, a senior organic chemist .

84
Penicillin Structure
  • By fall 1943, groups working at Oxford and at
    Merck had proposed two different structures
    penicillin molecule.
  • Chain and Abraham as well as by Robert Burns
    Woodward at Harvard four-membered beta- lactam
    ring lay at the heart of the penicillin molecule
  • Robinson instead proposed a structure based on
    oxazalone

85
Proposed Structures
Proposed oxazalone structure forpenicillin. The
oxazalone ringis shown in red.
Beta-lactam ring structure forpenicillin. The
beta-lactam ringis shown in red.
86
Newer Techniques to Study
  • New techniques for analyzing the structure of
    organic molecules - X-ray crystallography-
    practiced by Dorothy Hodgkin
  • In 1945 she was able confirmed Chain and
    Abraham's deduction. This evidence ran counter to
    Robinson's proposed structure for penicillin.

87
Production by Fermentation only
  • In 1957 John Sheehan created such a synthesis,
    but fermentation - the commercial production of
    penicillin and related antibiotics.
  • But the structural knowledge gained - developing
    penicillin-like antibiotics that were more
    effective, convenient to give and had fewer side
    effects.

88
Awards time
  • World War II ended and the Nobel Prizes in
    physiology or medicine distributed to Fleming,
    Florey, and Chain for their work on penicillin.

89
The Nobel Prize in Physiology or Medicine 1945
"for the discovery of penicillin and its curative
effect in various infectious diseases"
90
Penicillin-The master Drug
  • Pneumonia, syphilis, gonorrhea, diphtheria,
    scarlet fever and many wound and childbirth
    infections that once killed indiscriminately
    suddenly became treatable.
  • Deaths caused by bacterial infections plummeted

91
Words of Caution
  • By this time, even Fleming was aware that
    penicillin had an Achilles' heel.
  • He wrote in 1946 that "the administration of too
    small doses ... leads to the production of
    resistant strains of bacteria." It's a problem
    that plagues us to this day.

92
References
  • www.nobel.se
  • www.chemheritage.com
  • www.hisortylearningsite.co.uk
  • www.pbs.org
  • www.time.com
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