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SCIENTIFIC THINKING
Part II
Scientific Era (1600 AD – 2000 AD)
M N EL-Bolkainy
2013
OBJECTIVES
A The Search for a Method
(Scientific revolution)
B The Search for Etiology & Mechanisms
1. Gross pathology
2. Epidemiology
3. Microscopic pathology
4. Molecular pathology
(Biotechnology revolution)
THE SCIENTIFIC REVOLUTION
(1650 – 1800)
AIM
To replace the historic approach of
gaining knowledge based on
speculation by a more rational
objective method
THE PIONEER FOUNDERS
Francis Bacon
Galileo Galilei
Rene Descartes
England
Italy
France
(1561-1626)
(1564-1642)
(1596-1650)
THE ADVANCEMENT OF LEARNING
(Bacon, 1605)
THE VISION
•
•
•
Science and technology could transform the
world to the better
Science placed in unworthy (irresponsible)
hands could be destructive
Young scientists are more creative than old
ones
THE TWO WORLD SYSTEMS
(GALILEO, 1623)
ACADEMIC FREEDOM
The first to revolt against dogmatism by
supporting the heliocentric theory
QUANTITATION OF OBSERVATIONS
Hence allowing mathematical analysis
DISCOURSE ON METHOD
(Descartes, 1637)
SKEPTICISM
• We start by doubt (hypothesis) in order to
reach truth (conclusion)
• The only reliable knowledge is mathematics
• Except for God and Soul, the whole universe
is mathematical
• The aim of science is to control nature
THE STEPS OF SCIENTIFIC METHOD
1.
2.
3.
4.
5.
6.
7.
Definition of a problem
Collect data (observations)
Formulate a hypothesis
Test hypothesis (experiment)
Draw conclusions
Publication of results
Reproducibility by others
RESEARCH ERRORS
SAMPLE
Selected sample
Few cases
METHODS
Outdated reagents
Equipment error
Personal error
Statistical mischoice
CONCLUSION Invalidity
Causality error
THE TREE OF LIVE
Association or Causal Relation ?
Medieval concept
of genesis of
Animals from
plants
CRITERIA OF CAUSALITY
1. Strong association
2. Direct relation
3. Temporal relation
4. Explanatory mechanism
IMPORTANT QUESTION
• Can we gain knowledge without
applying the scientific method ?
ANSWER: YES
1. If experiment is impossible
(Darwin theory of evolution)
2. Scientific discovery by chance
EVOLUTION BY NATURAL SELECTION
AND SURVIVAL OF THE MOST FIT
Charles Darwin
(1809 – 1882)
Birds of same species
have different peaks in
different habitats
THE DURATION OF DARWIN
RESEARCH (1809 – 1882)
Step
Years
Observations
(Beagle tour)
Formulation of theory
(Inductive reasoning)
Publications:
1. The origin of species ( 1859)
2. Descent of man (1971)
Total
5
22
13
40
THE BROAD APPLICABILITY
OF DARWIN THEORY
Natural Science
Evolution of Species
Bacterial resistant strains
Cancer cell progression
Social Science
Religious, colonial,
class and ideological struggle
THE FUTURE OF SOCIAL STRUGGLE
1. END OF HISTORY
(Francis Fukuyama, 1992)
2. CLASH OF CIVILIZATIONS
(Samuel Huntington, 1996)
Judeo – Christian against Islam
The west against the reset
3. DIALOGUE AMONG CIVILZATIONS
(Mohamed khatami, 2000)
THE GENETIC CONFIRMATION OF
DARWIN THEORY
1. Discovery of chromosomes,
(Wilhelm Hofmeister, 1848)
2. Laws of heredity,
(Gregor Mendel, 1866)
3. Reproduction of Mendel laws,
(Hugo de Vries et al, 1900)
4. Mutation in Drosophila,
(Thomas Morgan, 1919)
5. Discovery of genes
(Walter Fiers, 1972)
MUTATIONS IN DROSOPHILA
(Thomas Morgan, 1919)
Differences in eye color
and length of wings
SCIENTIFIC DISCOVERIES BY CHANCE
1. Ovary – breast hormonal relation,
(Sir George Beatson, 1896)
2. Radioactivity of uranium,
(Antoine Becquerel, 1896)
3. Penicillin, the first antibiotic,
(Alexander Fleming, 1928)
4. Cancer Chemotherapy (Mustard gas, 1943)
(Gilman et al, 1946)
THE SEARCH FOR THE CAUSE AND
MECHANISM OF DISEASE
18th cent
18th cent
19th cent
20th cent
Gross Pathology (Morgagni, 1761)
Epidemiology (Pott, 1775)
Cellular Pathology (Virchow, 1858)
Molecular Pathology
(Multiple authors, 1950 – 2013)
“Clinicopathological
Correlation of 700
Autopsies”
GIOVANNI BATISTA
MORGAGNI
(1682 – 1771)
SEATS AND CAUSES
OF DISEASES, 1761
EPIDEMIOLOGY REVEALS ETIOLOGY AND
ALLOWS PREVENTION
ETIOLOGY
Scrotal Cancer is common
among chimney sweepers
(Sir Percival Pott, 1775)
PREVENTION
Legislation to ban
this occupation
ASBESTOS AND MESOTHELIOMA IN USA
Fabricated Research Delayed Banning
29 Years
1. Mesothelioma is related to asbestos
exposure (J. Eagner 1960)
2. Industry – Supported fabricated research to
prove otherwise
3. Carcinogenic risk firmly established (Roggli,
1987)
4. Production of asbestos was finally banned in
USA (1989), but, continued in developing
countries
TOBACCO SMOKING & LUNG CANCER IN USA
Money Talks / Thanks to Clever Lawyers
VAN GOGH, 1886
1. Smoking is related to
lung cancer
(Wynder,Doll,1950)
2. Lawsuit in USA
against tobacco
industry
3. Billions of dollars
compensation but
production continues
LIGHT MICROSCOPY
The Most Important Technology
of the 19th Century
THE INVENTION OF MICROSCOPE
EARLY INVENTORS
1. Compound microscope
(Galileo, 1610)
2. Simple microscope
(Leeuwenhoek, 1721)
MASS PRODUCTION
(Ernest Abbee,
Carl Ziess, 1900)
CONTRIBUTIONS
OF LIGHT MICROSCOPY
1. The cell theory (Schwan & Schleiden
1838)
2. Bacteriology (Ferdinand Cohn, 1853)
3. Cell Pathology (Muller & Virchow, 1858)
4. Cell division (W. Flemming, 1882)
5. Microsurgery (Carl Nylen, 1921)
6. Laser microsurgery (Strong & Jako, 1972)
CONTRIBUTIONS OF LIGHT MICROSCOPY
(Continued)
7. Phase Contrast (First Zernike, 1932)
8. Cytophotometry (T. Casperson, 1936)
9. Immunohistology (A. Coons, 1942)
10. Cytogentics (Tjio & Levan, 1956)
11. Molecular Genetics (Langer- Safer,1982)
12. Laser Capture Micro dissection, LCM
(Emmert – Buck, 1996)
• Cells are the units
of disease
• Microscopic
studies are more
precise than gross
examination
RUDOLF VIRCHOW
(1821 – 1902)
CELLULAR PATHOLOGY
1858
THE BIOTECHNOLOGY
REVOLUTION
(1950 – 2013)
AIM
To study biological phenomena at
molecular level, thus, revealing
mechanisms and allowing the
application of targeted therapy
THE FOUNDATIONS AND
PREREQUISITES OF
BITOTECHNOLOGY REVOLUTION
1.
2.
3.
4.
Well-trained staff
Team work (multidisciplinary)
Efficient equipments
Research funds
NATIONALITY OF 32 NOBEL PRIZEWINNERS
IN BIOTECNOLOGY (1950 – 2013)
American
15
British
4
French
4
German
3
Swiss
1
Australia
1
India
1
Japan
1
Egypt
1
Israel
1
RESEARCH SPENDING BY COUNTRIES
(Billions of US Dollars per year)
USA
China
Japan
Germany
405
297
160
70
India
Russa
Israel9
Egypt
(Wikipedia, 2011)
NB Figures included military spending
40
30
1
TECHNOLOGY INSTITUTES BY
COUNTRIES
USA
China
Japan
Germany
28
11
6
17
(Wikipedia, 2013)
India
Russa
Israel2
Egypt
16
9
2
BIOTECHNOLOGY NOBEL PRIZES
ARRANGED BY SUBJECT
Genomics
Proteomics
Infections and Cancer
Laser
Total
No
8
11
5
2
26
MOLECULAR SRUCTURE OF DNA
James Watson
(American)
Francis Crick
Maurice Wilkins
(British)
1962
DNA
MOLECULAR STRUCTURE & DOUBLE HELIX MODULE
ORGANIZATION
PACKAGE OF DNA
TO NUCLEOSOMES
AND CHROMOSOMS
THE BILOGIC DOGMA
DNA
mRNA
Protein
GENE REGULATION
1962
Francis Jacob & Jaques Monod
Activator and suppressors in E. Coli
2006
Roger Kornberg
RNA polymerase and nucleosome
2006
Anderw Fire
Epigenetic m-RNA silencing
2009
Elizabeth Blackburn
Telomerase
Regulator Genes
REGULATOR GENES MODEL
Activator
Suppressor
EPIGENETIC GENE CONTROL
“A change of gene expression
apart from mutation or the
conventional regulator gene
model”
CHROMATIN REMODELING
BY HISTONE ACETYLATION
Packed nucleosomes
(Silent genes)
Dissociated nucleosomes
(Active genes)
CYTOSINE METHYLATION
m-RNA SILENCING
POLYMERASE CHAIN REACTION
(PCR)
Kary Mullis
(American)
1993
PCR
A segment
of DNA is
amplified to
a million in
20 cycles
RESTRICTION ENDONUCLEASES
GENETIC ENGINEERING
Weber Arber
(Swiss)
1978
GENETIC ENGINEERING IN VITRO
Restriction Endonucleases
Diagnostic Probes
TARGETING GENES TO CHANGE
PHENOTYPE
(Genetic Engineering in Vivo)
2007
Mario Capeechi
Transfer of a gene to replace its
homologous gene in embryonic stem
cells (Knockout mice)
2012
John Gurdon & Shinya Yamanaka
Conversion of mature cell to a stem cell
(Genetic reprogramming)
applied in (Frog, Cheep, Mice and
Humane)
PROTEIN STRUCTURE
TRANSLATION, MODIFICATIONS,
TRANSPORT AND
DEGRADATION
2009
Venkatraman Ramakrishnan
Ribosome and protein synthesis
2013
James Rothman
Intracellular vesicle transport
2004
Aaron Ciechanover
Ubiquitin – Proteasome pathway (UPP)
of protein degradation.
PROINSULIN
Translation,
Modification,
And transport
THE BILOGIC PARADOX
DNA
(25,000 Genes)
mRNA
Protein (1000,000 Proteins)
EXPLANATION
1- One gene produces multiple proteins
2- One protein has different activities through
modifications
UBIQUITIN- PROTEASOME
PROTEIN DEGRADATION
SIGNAL TRANSDUCTION
1999
Gunter Blobel
Protein Signaling
2012
Brain Kobilka
G- protein – coupled receptors
SIGNAL TRANSDUCTION
CELL CYCLE CONTROL
Discovery of Cyclin Genes in Yeasts
Leland Hartwell
(American)
2001
CELL DIVISION CYCLE (cdc) CONTROL
IMMUNOLOGY
1972
1980
1984
1984
2011
Gerald Edelman
Structure of antibodies
Baruj Benacerrof
Major histocompatibility complex (MHC)
Georges Kohler
The hybridoma technology
Neils Jerne
Lymphocyte clonal selection
Bruce Beutler
Innate immunity (Dendritic Cells)
THE STRUCTURE OF ANTIBODIES
THE HYBRIDOMA
TECHNOLOGY
“The evil is used
to produce the good”
CLONAL SELECTION OF
B- LYMPHOCYTES
First encounter
(memory cells)
Second encounter
(Clonal expansion)
ANTIGEN PRESENTATION TO T-LYMPHOCYTES
IN ASSOCIATION WITH (MHC)
INFECTIONS AND CANCER
1966
1974
2005
2008
2008
Francis Rous
First virus-induced tumar
David Baltimore
Retrovirus oncogenesis (in vitro)
Barry Marshall
H. pylori and gastric cancer
Harold Hausen
HPV and Cervical Cancer
Luc Montagnier & Francois Bane-Sinoussi
HIV Discovery (AIDS)
ROUS RETROVIRUS-INDUCED
SARCOMA IN CHICKENS
LASER BEAM DISCOVERY
Charles Towns
(American)
1964
The most important
technology of
the 20th Century
GENERATION OF LASER BEAM
(Chromium)
PROPERTIES OF LASER BEAM
Single wave, coherent, parallel
Monochromatic, high energy, long distance
REGULAR LIGHT
APPLICATIONS OF LASER
Computers
Industry
Medicine
Show Light
Barcodes
Lunar Distance
Military
Biology
APPLICATION OF LASER IN BIOLOGY
1. Flow cytometry (W.H. Coulter, 1953)
2. Flow fluorescent microscopy (W. Gohde, 1968)
3. Laser capture micro dissection, LCM (E. Buck,
1995)
4. Photo thermal effect of laser on gold nano
particles (M. El – Sayed, 2006)
5. Dynamics of molecular reactions femtochemistry
(A. Zewail, 2009)
FLOW CYTO PHOTO METRY
Rapid multi-parameter
Analysis of thousands
of cells
LASER CAPTURE MICRODISSECTION
isolation of individual cells for study
FEMTOCHEMISTRY DYNAMICS USING
ULTRAFAST LASER
1999 Ahmed Zewail
• The Academic Discovery (1990)
(Femtosecond = 0.000,000,000,000,001)
• The Technologic application (2009)
(The 4-Dimentional EM)
“Technology determines
the power of nations,
not natural resources,
population size or ideology”