Muhammad Nabil El-Bolkainy

CHAPTER

1

Introduction, 1

Supernatural concepts, 1 Empirical method, 2 Natural concepts, 2 The philosophy of logic, 2 Dogmatism, 2

Arabs and renaissance, 3 The scientific method, 5 Science by other ways, 6 Etiology and classification of disease, 6

Statistical methods, 7 The biotechnology revolution, 7 The impact of science on human life, 7

Outline

INTRODUCTION

Science is defined as true knowledge about nature

and the universe. The word comes from Latin, scien-tica meaning knowledge. Conversely, technology is the application of science for practical purposes (useful or harmful). Thus, the atomic formula of Ein-stein (E=Mc2) is an example of science. It relates en-ergy (E) to atomic mass (M) and speed of light (C). However, to build an atomic reactor or to make an atomic bomb is technology. Obviously, technology is much more important than science.

Advances in our knowledge on nature and disease was linked to the progress that has been made in sci-entific thinking. The ancient history of man starts from the first recorded writings (3600 BC) and ex-tends to about (500 AD). The middle age extends from the 6th to 16th centuries. The scientific method introduced in 1600 AD represents an important turning point in scientific thinking. Accordingly, the history of mankind can be divided into two main pe-riods (epochs), namely: a prescientific period of 5200 years (3600 BC to 1600 AD), and a short scientific period of only 416 years (1600 AD to 2016 AD). The present chapter reviews the history of scientific think-ing and the recent biotechnology revolution, with emphasis on advances made in biology and medicine..

THE PRESCIENTIFIC PERIOD

(3600 BC to 1600 AD)

In ancient history, almost all concepts on nature and disease were wrong. In addition, the methods adopted to reach knowledge were also primitive, time consuming and unproven. In case of diseases, misconcepts were dangerous, since they ultimately led to misdiagnosis and mismanagement. The fol-

lowing are examples of these concepts which were generally believed and practiced on a large scale dur-ing that epoch.

Supernatural Concepts

At the dawn of history, man believed that diseases were due to evil spirits or punishment from gods. According to this concept, there is only one cause for all diseases and man is helpless to confront them alone, and hence has to turn to priests and magicians who prescribed sacrifices, incantations, cautery, and praying (Fig 1-1). In addition, a wrong theory hinders progress of science. If sickness is thought to result from evil spirits, there is no need to search the body for natural causes of disease.

Fig 1-1 Supernatural concepts. An Ancient Egyptian seek-ing cures from Horus, the God of healing. The eye of Horus was a symbol of godly protection.

Empirical Approach This is based on experience, obtained through trial

and error and careful observation. The Ancient Egyp-tians made significant accomplishments by this ap-proach, including: (1) tissue preservation or embalm-ment using wine for fixation and natrun salt for tissue dehydration, (2) obtaining drugs for different diseases from different plant extracts, and (3) building pyra-mids of gradually increasing size. However, it is note-worthy that the empirical approach is very time con-suming. Thus, it took the Egyptians almost 400 years to build the perfect kufu pyramid at Giza (2560 BC) after several trials of imperfect ones.

Natural Concepts The Humoral Theory

The Ancient Greek philosophers, not satisfied with the mythology of their time, turned their atten-tion to nature. Hippocrates (460-375 BC) was the first to consider disease a result of natural rather than su-pernatural causes, namely, an imbalance of the four fluids or humors of the body: the blood, mucus, yel-low bile and black bile. Aristotle (384-322 BC) was the first to link the four humors of the body to the four elements of nature (Fig 1-2). Although unsound by our present knowledge, the humoral theory intro-duced for the first time a natural environmental mechanism of disease and was accepted by the medi-cal profession in Europe for almost 1900 years.

The Philosophy of Logic

Aristotle (384-322 BC) is considered one of the greatest natural scientists (Fig. 1-3). He emphasized the freedom of thinking, that any problem in nature or human behavior could be a subject of study and all problems are the result of natural causes. He intro-duced the philosophy of logic, to obtain knowledge through reasoning or posing statements (premises) which lead to a conclusion. He introduced the term validity to describe the extent to which a conclusion corresponds accurately to the real world. Aristotle described two types of reasoning, namely:

(1) deductive reasoning, which starts by a generalization (a hypothesis) then reaches a specific conclusion, and (2) inductive reasoning which starts by multiple observations then ends by a generalization (untested hypothesis). He considered repeated cycles of de-duction and induction will lead to advance of knowledge.

Dogmatism This describes adherence to personal opinions and

disregarding others. Concepts of a dogmatic master must be accepted without any arguments. This atti-tude turns science to a fixed principle or doctrine. Two types of dogmatism are recognized:

Religious Dogmatism. The best example is the Ro-

man Catholic Church with its dominant power in Me-dieval Europe (200 AD to 1500 AD). The theology of that time was introduced by the writings of Saint Au-gustine (City of God, published 410 A). Accordingly, the church is above the state, faith above knowledge, disease is a punishment from god and theology is the queen of all sciences. Church concepts about nature must be obeyed, and those who disobey are consid-ered heretic and executed. In this atmosphere, a pro-gressive deterioration of science in Europe occurred for 1300 years.

At that time, two conflicting theories were pro-posed about the center of Universe and whether the earth move or not. According to the geocentric mod-el (held by Ancient Greek and Catholic Church) the earth is the center of universe, the sun and planets

Fig 1-2 The Humoral theory. The relation of the four

body humors to the four environmental natural elements

Fig 1-3 Aristotle (384-322 B.C.). The founder of the phi-losophy of logic and world greatest natural scientist .

El-Bolkainy Surgical Pathology 2

rotate around. Conversely, an opposite view, the heli-ocentric model, was proposed by the Polish astrono-mer Copernicus, that the sun is the center of universe, the earth and planets rotate around. He completed his book in 1543 AD, but hesitated to publish it for fear of difficulties with the church.

Authoritative Dogmatism. Galen (Clarissimus Ga-

lenus, 130-201 AD) was the leading physician of the Roman Empire. He wrote about 300 books and cured the Emperor from fever, hence was considered an infaliable authority. But Galen had two pitfalls. First, he was an enthusiastic supporter of the humoral theory and advocated systemic treatment (bleeding and purgation) to eliminate the excessive humor and correct the imbalance. Second, Galen studied anato-my by animal dissection (human autopsy was prohib-ited at that time) and applied the findings to man. Thus, according to Galen, the human body contained a five-lobed liver, a horned uterus and a hole in the septum of the heart. No body dared to object these dogmatic statements, and these erroneous concepts dominated medical thought in Europe for almost 1500 years after his death.

The Arabs and Renaissance

In contrast to the gloomy picture in Europe, there was a remarkable development of intellectual activity by Arabs during the Islamic Empire (900-1200 AD). The Arabs discovered and translated the work of great Greek philosophers into Arabic and Latin. They also added original scientific achievements of their own in different fields. All these translated works were introduced to Europe through Spain, thus help-ing the rebirth of science (Renaissance) in the 16th century. Two scientists of this period deserve special mention in view of their remarkable contributions.

Hassan Ibn AL-Haytham, born in EL-Basra, Iraq, is

considered the first and possibly the greatest Islamic scholar (Fig 1-4). In his work (the Book of Optics, 1021 AD) he described the steps of scientific method (as we know it now), 500 years before the scientific revolution in Europe. He criticized the logical ap-proach in scientific inquiry and favored experimental inductive method. He proved by experiment in a dark room that light travels in a linear manner. Most prob-ably, the work of Newton on Light was directly built upon the ideas of Ibn AL-Haytham.

Andreas Vesalius is a remarkable scientist of Re-

naissance (Fig 1-5), a professor of anatomy at Padua University, Italy. He was the first in 1539 to do an autopsy on a human body of an executed criminal. He noticed that the organs did not correspond to the historic description of Galen (no black bile in spleen, no hole in the heart and no five lobes in liver). At the age of 29, he published his monumental anatomic studies (The Fabric of Human Body, 1543). The im-mediate effect was the downfall of the Greek humor-al theory of disease. Subsequent effects were advanc-es made in surgery and gross pathology.

THE SCIENTIFIC ERA

The scientific era extends only over the past 400 years. The 17th century was the period of developing a new method for scientific investigations (the scien-tific method). In the 18th and 19th centuries, a search was made to identify the etiology and classification of disease (gross and microscopic pathology). Finally, the 20th century was the period of improving therapy and revealing mechanisms of diseases (the biotech-nology revolution). Contributions of the pioneer sci-entists of the scientific revolution are presented in (Table 1-1).

Fig 1-4 Hassan Ibn Al-Haitham (965-1040, Iraq). The true father of the scientific method and optics

Fig 1-5 Andreas Vesalius (1514-1564, Belgium). The founder of human anatomy and the first to do human autopsy

Scientific Thinking 3

Scientist (year) Contribution

Galileo Galilei (1610) Invention of compound microscope

William Harvey (1628) Discovery of blood circulation

Giovanni Morgagni (1761) Clinicopathological correlation

Percival Pott (1775) Chimney sweepers scrotal cancer

Edward Jenner (1796) Small pox vaccination

Xavier Bichat (1800) The tissue concept

Theodor Schwann and Jacob Schleiden (1838)

Discovery of cells as units of living organisms

William Morton (1846) Discovery of ether anaesthesia

Rudolf Virchow (1858) Cells are the units of disease

Charles Darwin (1859) Evolution by natural selection

Louis Pasteur (1861) Discovery of bacteria and fermentation

Gregor Mendel (1866) Laws of heredity

Joseph Lister (1867) Antiseptic techniques in surgery

Robert Koch (1870) Bacterial cause of disease

William Halsted (1891) Radical surgery for breast cancer

Wilhelm Roentgen (1895) Discovery of X-rays

George Beatson (1896) Ovary- Breast hormonal relation

Antoine Becquerel (1896) Radioactivity of uranium

Marie curie (1898) Discovery of radium

Ernest Abbee (1900) Carl ziess microscopes

Thomas Morgan (1919) Mutation in Drosophila

James Ewing (1919) Modern classification of cancer

Alexander Fleming (1928) Penicillin, the first antibiotic

Otto Warburg (1931) Aerobic glycolysis in cancer cells

Max Knoll and Ernest Ruska (1931) Discovery of electron microscope

Charles Huggins (1941) Estrogen therapy for prostatic cancer

George Papanicolaou (1943) Cytologic diagnosis of uterine cancer

Alfred Gilman (1946) Mustard gas, the first cancer chemotherapy

ErnestWynder and Richard Doll (1950) The relation of smoking to lung cancer

Wallace Coulter (1953) Flow cytometry

Chi-Chang Kao (1956) Advanced linear accelerator

George Mate (1958) Bone marrow transplantation

Eagner and Wagner (1960) Etiologic relation of asbestos and mesothelioma

James Holland and Vincent Devita (1970) Curable combination chemotherapy

Strong and Jako (1972) Laser microsurgery

Nicholas lyndon and Brian Druker (1993) Gleevec (Imatinib) the first antikinase targeted therapy

Michael Emmert Buck (1996) Laser capture microdissection

Mostafa EL-Sayed (2006) Nanogold photothermotherapy for cancer

Ahmed Zewail (2009) The four dimentional electron microscope

Table 1-1 Pioneers of Science in Biology and Medicine (1620-2009)

El-Bolkainy Surgical Pathology 4

The Scientific Method

The scientific revolution aimed at replacing the historic approach of gaining knowledge based on speculation, by a more rational objective method. The three pioneer founders are: Sir Bacon, a British politician, Galileo, an Italian scientist and astronomer, and Descartes a French philosopher and mathemati-cian. Their common objective was to liberate science from philosophy and dogmatism.

Sir Francis Bacon (Fig 1-6) in his work (Advacement of Learning, 1605) predicted that sci-ence and technology could transform the world to the better, but science will be dangerous when placed in unworthy hands. He rejected Greek methods of the past and advocated proper experiments.

Galileo Galilei (Fig 1-7) was the first to do experi-ments and quantitate data. He was a symbol of aca-demic freedom by revolting against church concepts and adopting the heliocentric theory that the earth moves around the sun, despite house arrest punish-ment by church authorities.

Rene Descartes (Fig 1-8) in his work (Discourse on Method, 1637), he invented a skeptical approach to scientific thinking with systematic doubt of all our accepted knowledge since conclusions were based upon subjective unreliable observations. Descartes stressed that we should start by doubt not with belief (the reverse of the attitude of St. Augustine), and we should build our knowledge on solid facts and mathe-matics.

The steps of scientific method are presented in (Table 1-2). When a hypothesis is reproduced by others, it becomes a theory, whereas its global recog-nition and applicability to different phenomena it becomes a general law. In experimental design, all

variables must be studied in the same experiment, which must include a control (James Lind, 1753). Se-lection of cases from a large series must be at ran-dom (CS Peirce, 1885).

There are three main sources of experimental er-rors, namely: (1) sample error which may result from non-representative sample due to selection or few number of cases in the study groups, (2) experimental errors of several causes such as: outdated reagents, equipment error, personal error or a mischoice of a statistical method, and (3) conclusion errors which may be due to invalidity or causality error. The latter oc-curs when two observations are frequently seen in association, so that it is difficult to determine if it is a mere association or etiologic relation (Fig 1-9). The criteria of etiologic relation must include a strong direct relation, temporal relation, and available mech-anism to explain the etiologic relation.

Fig 1-6 Francis Bacon (1561-1626, England). Predicted the value and haz-ards of scientific methods

Fig 1-7 Galileo Galilee (1564-1642, Italy). Pioneer of academic freedom and first to quantitate data

Fig 1-8 Rene Descartes (1596-1650, France). The founder of scien-tific skepticism

Scientific Thinking

Table 1-2 The Steps of Scientific Method

1. Definition of a problem

2. Review of Literature

3. Propose a hypothesis

4. Experiment to test hypothesis

5. Data analysis

6. Reach a definite conclusion

7. Publication of study

8. Reproducibility by others

5

Science By Other Ways

Isaac Newton (1642-1727), an English physicist

and mathematician, is considered the greatest and most influential scientist. His scientific approach is to turn observations and data directly to a unified theory. He published his great work (The Principa, 1687) in which he presented his law of gravitation, as well as, the laws of motion. He used his mathe-matical tools of calculus (not the scientific method). Newton showed how these laws could be used to solve not only usual mechanical problems, but also predict precisely the motions of planets around the sun.

Charles Darwin (1809-1882), an English biologist

and geologist, published his theory of evolution by natural selection in 1842 which caused a biological revolution. This theory was established after 40 years of hard work. This included 5 years of data collection from nature by sailing on the ship Beagle. In addition, 35 years were necessary to formulate the theory and publish books. As with the case of New-ton, multiple observations were used to form a uni-fied theory (inductive reasoning). His theory is appli-cable to natural science, especially biology, as well as,

social and political sciences. Three other important scientific discoveries

were made by just a chance, namely: (1) the discov-ery of X-ray radiant energy (W Roentgen, 1895), (2) the discovery of the therapeutic effect of war gas (nitogen mustard) on lymphoma (A Gilman, 1946), and (3) the discovery of the antibiotic Penicillin (A Fleming, 1928).

Etiology and Classification of Disease

Infectious diseases were originally thought to arise from pollution (the miasma theory). The relation of bacteria and viruses to disease (Germ cell theory) was established in the 19th century through the ef-forts of three pioneer scientists: (1) Louis Pasteur(1822-1895) a French chemist and biologist, (2) Rob-ert Koch (1843-1910), a German microbiologist and (3) Sir Joseph Lister (1827-1912), a British surgeon. Pasteur and Koch identified several types of organ-isms and called them pathogens. Conversely, Lister emphasized on practical applications (antiseptic sur-gery) using phenol for sterilization. Even before the identification of viruses, Jenner vaccinated against smallpox in (1796) and Pasteur vaccinated against rabies in (1885). Viruses were observed only after the invention of the electron microscope (knell and Rus-ka, 1931) and their exact typing made possible by the molecular techniques of the 20th century.

Epidemiologic studies also revealed etiology. Thus, in 1775, Sir Percival Pott an English physician, report-ed on the development of scrotal skin cancer in adults who had been engaged as chimney sweepers during their childhood. He suggested chimney soot (tar) as a causative agent. This report helped to es-tablish laws for the protection of children in hazard-ous occupations, a pioneer step in cancer prevention. The diagnosis and classification of diseases passed into two stages, namely: gross then histologic pathol-ogy.

Morgagni (Fig 1-10), a professor of anatomy, uni-

versity of Padua Italy, published his monumental work (On the Seats and Causes of Disease, 1761). It contained clinical data and autopsy findings of 700 cases. This was the first time to relate diseases to local anatomic sites and gross features. Abernethy in 1811 introduced a classification of diseases according to gross appearance and recommended it as a guide of therapy. This system was strongly admired and widely practiced by surgeons. However, the inven-tion and widespread use of microscopes, ultimately led to the development of a better classification sys-tem. Thus, in 1858, Rudolf Virchow (Fig 1-11) consid-ered, cells as the units of diseases and advocated bi-opsy as a diagnostic procedure. After an initial oppo-sition from surgeons, biopsy and histopathology have become the gold standard of diagnosis and classification of diseases.

Fig 1-9 The tree of life. Medieval concept of genesis of animals (ducks and fish) from plants (fallen leaves). We know now that this is a mere association not etio-logic relation

El-Bolkainy Surgical Pathology 6

Statistical Methods

The development of science of biostatistics by the end of 19th century introduced precise objective tool for data analysis. This included: correlation of two quantitative variables (Galton, 1869) and X2(chi-square) test for qualitative data (Pearson, 1900), Me-ta analysis is a statistical method (weighed average) used when data from different centers are pooled together (K Pearson, 1904) and student test of sig-nificance of difference between means (Student, 1908). Two advanced statistical methods were devel-oped later, namely: survival analysis of treatment outcome (Kaplan and Meier, 1958) and multivariate analysis (Cox, 1972). The latter, tests interaction among multiple variables and identify the independ-ent variables which are truly significant.

The Biotechnology Revolution

Biotechnology revolution started in 1950. The aim was to study biologic phenomena at molecular level, thus revealing mechanisms, improving diagnosis and allowing the application of targeted therapy. The prerequisites of a biotechnology revolution include: available well-trained staff, team work, multidiscipli-nary approach, efficient equipment and generous research funds. Such requirements are usually availa-ble at technology institutes rather than universities. Key scientific discoveries were made in several fields including: molecular genetics, immunology, microbi-ology and proteomics. All these remarkable studies were awarded Noble Prizes (Table 1-3).

THE IMPACT OF SCIENCE ON HUMAN LIFE

The impact of science on human life is evident by

time trend analysis of registered data from USA (Carolina Demography). The overall mortality rate declined markedly over the 20th century by 54%. In 1900, the average life expectancy was 47.3 years, whereas, in 2010 it increased to 78.7 years. The rank-ing of leading causes of death has also undergone significant change in the 20th century (Table 1-4). Thus, in 1900, the top two causes of mortality were infections and vascular diseases, whereas, in 2010 the leading mortality was from vascular diseases and can-cer. Infectious diseases were almost eliminated, thanks to antibiotics, sanitation and immunization. Noninfectious diseases (such as diabetes, senility and nephropathies), have merged as a new public health challenge.

In cancer patients, a significant increase of curabil-ity was accomplished over the 20th century (Fig 1-12). Thus, during the period (1900-1950) surgery was the only treatment modality available and 5-year sur-vival in 1950 was 50%, whereas, in 2015 survival was 67% (SEER data, 2015). This increase in survival is the result of breakthrough therapeutic discoveries, namely: the use of combination chemotherapy, the invention of advanced linear accelerators, bone mar-row transplantation and targeted therapy.

Fig 1-11 Rudolf Virchow (1821 – 1902, Germany). He introduced cellular basis of diseases and advocated diagnostic biopsy.

Fig 1-10 Giovanni Batista Morgagni (1682 – 1771, Italy). The founder of gross pathology and clinicopathological correlation.

Scientific Thinking 7

Year Winner Nationally Awarded for

1962

J Watson

F Crick, M Wilkins

American British

Structure of DNA

1962 F Jacob, J Monod French Gene regulation in E coli

1964 C Towns American Discovery of laser beam

1966 F Rous American Oncogenic Virus in chickens

1972 G Edelman American Structure of antibodies

1974 D Baltimore American Retrovirus oncogenesis (in Vitro)

1978 W Arber Swiss Restriction endonucleases (genetic engineering in vitro)

1980 B Benacerrof American Major histocompatibity complex

1984 N Jerne British Lymphocyte clonal selection

1984 G Kohler German Hybridoma technology, (monoclonal antibodies)

1993 K Mullis American Polymerase chain reaction (PCR)

1999 A Zewail Egyptian Femtochemistry dynamics, 4-dimentional electron microscopy

1999 G Blobel German Protein signaling

2001 L Hartwell American Cell cycle control (cyclin genes)

2004 A Ciechanover Israeli Ubiquitin-Proteasome protein degradation

2005 B Marshall Australia H pylori and gastric cancer

2006 R Kornberg American RNA polymerase and nucleosome

2006 A fire American Epigenetic m-RNA silencing

2007 M Capeechi Italian Gene cloning (Genetic engineering in vivo)

2008 H Hausen German HPV and cervical cancer

2008 L Montagnier, F Bane-Sinoussi

French HIV discovery (AIDS)

2009 E Blackburn Australian Telomerase discovery

2009 V Ramakrishnan Indian Ribosomes and protein synthesis

2011 B Beutler American Innate immunity (dendritic cells)

2012 B Kobilka American G-protein-coupled receptors

2012 J Gurdon S Yamanaka

British Japanese

Genetic reprograming (change of mature cell to stem cell)

2013 J Rothman American Intracellular vesicle transport

Table 1-3 Noble Prize Winners of the Biotechnology Revolution

El-Bolkainy Surgical Pathology 8

Table 1-4 Comparison of Causes of Mortality in 1900 versus 2010

(Carolina Demography, USA.) Vascular includes: cardio vascular and cerebrovascular dis-eases, Noninfectious includes: diabetes, senility and nephropa-thies, Trauma includes: accidents, war and suicidal cases.

In conclusion, the application of scientific method

had a dramatic effect on human life, as predicted by sir Francis Bacon (1605). Thus, the industrial revolu-tion increased national income and scientific revolu-tion improved the quality of life. However, unfortu-nately, advanced technology when placed in irrespon-sible hands resulted in two global wars (1914 and 1939) with casualities of 38 millions and 60 millions respectively.

REFERENCES De Young G: Scientific Thinking, 2nd edtion, The

American University of Cairo, 1992. Hart M H: The 100, A Ranking of the Most Influen

tial Persons in History, A and W publishers, NY, 1978.

Ronan CV: The Cambridge Illustrated History of the World Science, Cambridge University Press, NY and London, 1983.

Singer C and Underwood EA: A short History of Medicine. Oxford University Press, NY and Ox-ford, 1962.

1900 2010

Infections (43.5%) Vascular (39.3%)

Vascular (26.5%) Cancer (31%)

Noninfectious (15%) Noninfectious (18.5%)

Trauma (7.8%) Trauma (8.5%)

Cancer (7%) Infections (2.7%)

Fig 1-12 Advances in 5 years survival in cancer patients during the 20th century and its relation to breakthrough discoveries in

therapy. (SEER Data, USA). A, Radical surgery, William Halsted (1891) , B, Stanford advanced linear accelerator, Chi-

Chang Kao (1956), C, Bone marrow transplantation, George Mate (1958), D, Curable combination chemotherapy, James Hol-

land and Vincent Devita (1970), E, Gleevec (Imatinib) the first targeted therapy, Nicholas Lyndon and Brian Druker

(1993) .

Scientific Thinking 9