1. MECHANISMS OF DISEASE Historical Introduction A00: GENERAL BODY & UNSPECIFIED Frank W. Stitt MD FRACP Vanuatu College of Medicine © Copyright 2002. Frank W. Stitt MD FRACP. All rights reserved. Hippocrates

2. 3-31-1999Disease Mechanisms 2 CONTENTS A. INTRODUCTION B. THE EARLIEST THEORIES C.THE HIPPOCRATIC AFTERMATH D. THE RENAISSANCE E. THE SCIENTIFIC REVOLUTION F. THE SYNTHESIS OF IDEAS G. DEFINING DISEASE H. IDEAS INFLUENCING CLINICAL PRACTICE J. NEWER DISCIPLINES K. FINAL SUMMARY

3. 3-31-1999Disease Mechanisms 3 SUMMARY (I) Development of concepts about disease in the context of philosophy & observational technology of the time At first: causes of disease linked to punishment & retribution Then: the Rationalist movement and advances in scientific instrumentation stimulated a fresh approach As instrumentation improved, allowing empiricism, new methodology used to describe normal functions, then disease states

4. 3-31-1999Disease Mechanisms 4 SUMMARY (II) Infectious agents, long suspected, identified following advances in microscopy Development of biochemistry, then immunology, provided new insights, with understanding of molecular processes and genetics Recent explosion in knowledge stems from new scientific instruments and computer technology, allowing acquisition and communication of information much easier

5. 3-31-1999Disease Mechanisms 5 A. INTRODUCTION Ideas about disease have evolved over 25 centuries Medicine's roots in superstition & occult (“voodoo”) Primitive society and "evil spirits“: still today The body is possessed by an evil spirit because of sin or breaking a taboo, or because an enemy has willed it Stigma was attached to illness (still is) Illness as punishment –Hubris: offending the gods of the Greeks –  Nemesis: the punishment Hidden forces behind illness and disease (AIDS, smoking- related diseases

6. 3-31-1999Disease Mechanisms 6 CHANGE IN IDEAS Coming of rationalist thought in the West with the Greeks Development of scientific instrumentation New technology for information: –Acquisition –Storage –Transfer –Retrieval

7. 3-31-1999Disease Mechanisms 7 INFORMATION TRANSFER Word of mouth (e.g. medieval troubadors): knowledge limited to very few Decline in influence of the church from challenges to faith Next: writing & printing The printing press –Books first, then –Scientific journals (17-18th century) –Huge growth in the 20 th century Electronic computers

8. 3-31-1999Disease Mechanisms 8 B. THE EARLIEST THEORIES Ancient civilizations of China, Egypt, & India had well- developed systems of medicine Western traditions: Hippocrates and the Greeks (460-377 BC) Code of practice (the “oath”) Theories of causes of disease based on observation –Intrinsic: constitutional makeup of the person –Extrinsic: environmental agents Balance of four humors: blood, bile, black bile, & phlegm Heroclitus (ca. 500 BC): matter in a state of flux –Fire and water External causes of disease as "miasmas", or polluting agents

9. 3-31-1999Disease Mechanisms 9 C.THE HIPPOCRATIC AFTERMATH Galen (129-200 AD): Greek physician who moved to Rome Took humoral hypothesis and created four temperaments: –Sanguine; choleric; melancholic; and phlegmatic –Each temperament predisposed to group of diseases Introduced a structural dimension -- beginnings of anatomy (but mostly wrong)

10. 3-31-1999Disease Mechanisms 10 D. THE RENAISSANCE Flowering of arts and culture that ended the Dark Ages: parallel in science and medicine Anatomical dissection in Bologna and Padua (Vesalius 1514-64); seeds of pathology Frascatorius (1478-1553): possibility of contagions with “seeds of disease” French physician Jean Fernel (1497-1558): classification of disease based on location & localization – based on autopsies First rationalism, disease not result of superstition

11. 3-31-1999Disease Mechanisms 11 PARACELSUS Swiss physician (1493-1541) Equivocal about origins of disease, stressing spiritual and occult Through travels and teaching reduced influence of humoralist theory of Galen Encouraged research and experiment Contributed to thinking about pathological mechanisms and external causes of disease with local more than systemic effects

12. 3-31-1999Disease Mechanisms 12 E. THE SCIENTIFIC REVOLUTION Foundations of modern science in latter Renaissance Observational astronomy: Copernicus (1473-1543) Galileo (1564-1642) and findings from refracting telescope Kepler (1571-1630) and astronomical calculations leading to... Newton (1642-1727): science and mathematics (e.g. Leibnitz & calculus)

13. 3-31-1999Disease Mechanisms 13 PHILOSOPHICAL COUNTERPART To the scientific ferment Englishman Francis Bacon (1561-1626) –pioneer of modern scientific method –based on experimentation as well as observation –empirical Frenchman Rene Descartes (1596-1650) –Cogito ergo sum (“I think, therefore I am”) –focus on the observational –living organisms obey the laws of physics –man has a mind separate from the body

14. 3-31-1999Disease Mechanisms 14 The Scientific Revolution: Medicine Harvey (1578-1637): greatest medical scientist –Used experimental method to ascertain... –“Action, function, and purpose" of the parts –Described the circulation of the blood –Starting point was anatomical, but his work is the foundation of modern physiology Invention of the microscope By end of 17 th century, all basic disciplines discovered except biochemistry Sydenham (1624-89): the “English Hippocrates” –Need for systematic classification of disease –Each disease had a specific cause (“etiology”), thus its own specific cure

15. 3-31-1999Disease Mechanisms 15 F. THE SYNTHESIS OF IDEAS Rise of various disciplines that contribute to knowledge about the origins of disease 1.The Classification of Disease 2.The Morphological Basis of Disease 3.Infection & Clinical Microbiology 4.Immune Mechanisms 5.The Genetic Connection 6.Metabolic Disorders and Chemical Pathology 7.The Physiological Approach

16. 3-31-1999Disease Mechanisms 16 1. DISEASE CLASSIFICATION Thomas Sydenham (1624-89): the "English Hippocrates" Systematic description and classification of disease Categorized according to presentation Each disease has a specific cause (etiology) and cure Linnaeus (1707-78): taxonomy of plant and animal kingdoms Francois Boissier de Sauvage (1706-67): symptom-based Cullen (1710-90): –3 classes of disease -- pyrexia, neurosis, cachexia –Based on vital, animal, & natural functions –Fourth class: local disease

17. 3-31-1999Disease Mechanisms 17 1. DISEASE CLASSIFICATION Subsequently elaboration and refinement based on synergy of clinical and non-clinical studies Advances in biology, physics, & chemistry General pathology mid-19 th century Molecular biology 100 years later

18. 3-31-1999Disease Mechanisms 18 2. MORPHOLOGICAL BASIS OF DISEASE Morbid anatomy: seeds of general pathology in 15 th century Desire to correlate autopsy findings with clinical diagnosis Morgagni (1682-1771): case histories linked to autopsy findings Bichat (1771-1802): –Microscopic histology and pathology –Organs are made up of tissues

19. 3-31-1999Disease Mechanisms 19 2. MORPHOLOGICAL BASIS OF DISEASE Virchow (1821-1902): Pathologic process centered on the cell (“Omnis cellula e cellula”) Pathological cell is based on the normal cell Advances in microscopy and special stains Rejection of humoralism (Galen)

20. 3-31-1999Disease Mechanisms 20 IMAGING TECHNOLOGY Microscope, biopsy, special stains Electron microscopy Immunocytochemistry Advances in imaging –radiography –radioisotopes –CT/MRI/PET

21. 3-31-1999Disease Mechanisms 21 3. INFECTION Based on cellular pathology Long historical antecedents with contagions based on "miasmas" Beginnings of epidemiology (Frascatorius) Fevers might be contagious, but were disease processes in themselves rather than manifestations Disease prevention is possible without understanding cause or transmission by live agents –Smallpox vaccination –Cholera epidemics (the "Broad Street pump") Microscope transformed cellular pathology

22. 3-31-1999Disease Mechanisms 22 CLINICAL MICROBIOLOGY Pasteur (1822-95): "Germ theory" Henle (1809-85, teacher of Koch (1843-1910) Technology: microscopy, staining and culture Living agents of microscopic size as a cause of disease (e.g. anthrax) Staining and culture methods allowed new discoveries Pervasive effect of germ theory in the 20th century Viruses, then prions discovered

23. 3-31-1999Disease Mechanisms 23 4. IMMUNE MECHANISMS Born of microbiology Microbial agent as stimulus for the immune response Bacteria cause toxins, anti-toxins form the remedy Metchnikoff (1845-1916): return to humoralist theory Concepts of immune mechanisms as cause of disease Concept of body able to recognize its own components Landsteiner (1868-1943) and main blood groups Discovery of histocompatibility antigens on leucocytes –Allergy, autoimmunity

24. 3-31-1999Disease Mechanisms 24 5. THE GENETIC CONNECTION Mendel (1822-84) and the laws of genetics Observation that some diseases run in families (“heriditary”) Bateson (1861-1926) and Garrod (1857-1935) –related heredity to metabolic disease –genetic basis for biochemical abnormalities Identification of chromosomes and the human karyotype Localization of genetic information to DNA Breaking the genetic code (Watson and Crick), allowing inherited disease to be understood at the molecular level Gene mapping leads to understanding of disease

25. 3-31-1999Disease Mechanisms 25 6. METABOLIC DISORDERS & CHEMICAL PATHOLOGY Introduction of chemistry into medicine Distinguishes the modern era from previous studies Aretaeus (c. 100 AD) and diabetes mellitus ("sweetness") Chemistry emerged from alchemy in early 17th century Thomas Willis (1621-75) and sugar in diabetic urine 20th century: concept of "biochemical lesion“ at cellular & sub-cellular level Emergence of molecular biology linking genetics and biochemistry Based on "big science" technologies

26. 3-31-1999Disease Mechanisms 26 7. THE PHYSIOLOGICAL APPROACH Harvey is the father of human physiology (circulation) Ancients speculated: he observed and experimented, and constructed hypotheses to be tested further Malphigi (1628-94) & discovery of capillaries by microscopy Further progress by: Observation  experimentation  hypothesis Next leap: Claude Bernard (1813-78) and milieu interieur –Body functions as an integrated whole –This integration works to maintain stability Concepts of homeostasis and the body as machine He extended the range of experimentation

27. 3-31-1999Disease Mechanisms 27 G. DEFINING DISEASE Disease produces morbidity Illness is a manifestation of disease, as judged by the sufferer or a clinical observer Disease as dysfunction relative to some norm

28. 3-31-1999Disease Mechanisms 28 H. IDEAS INFLUENCING CLINICAL PRACTICE The "germ theory" and antibiotic use (Koch) The "body as a machine" (Bernard) Loss of observational skills (Louis)

29. 3-31-1999Disease Mechanisms 29 J. NEWER DISCIPLINES The rise of pharmacology and focus on drug treatment of disease processes Cell and molecular biology resulting from the Human Genome Project

30. 3-31-1999Disease Mechanisms 30 K. FINAL SUMMARY Prior to the Greeks (5 centuries BC), supernatural forces caused disease Hippocrates and Galen: descriptions of disease and their cause; the physical approach Galenic system of the four humors Development of general scientific method and philosophy in the Renaissance Mechanics of disease: anatomy and morbid anatomy, histopathology Biochemistry emerged from medieval alchemy Recent (17 th century) physiological approach to disease Modern developments in microbiology, immunology, and genetics, plus computing

31. MECHANISMS OF DISEASE Historical Introduction A00: GENERAL BODY & UNSPECIFIED Frank W. Stitt MD FRACP Vanuatu College of Medicine © Copyright 2002. Frank W. Stitt MD FRACP. All rights reserved. Hippocrates