Development of the Field of Pathology

Historical Progression of the Field of Pathology

Egypt

1700 BC to 1601 BC

Clear written evidence of contemplation of the nature of disease is documented in Egyptian Papyrus that include detailed references to bone and soft tissue diseases and parasitic infections. These observations were made in concert with the development of embalming techniques that involved dissections of humans and animals and would have requiered extensive anatomical knowledge. Egyptian medicine continued to develop through the rise of Greek civilization and was known to and described by the Greek historian Herodotus.

Click on the image to the left to read a 1930 translation of the Papyrus Ebers provided by the University of Chicago Oriental Institute's on-line archives - an absolute wealth of historical text. There are several papyrus text, this one is dated to 1550 BC, covering aspects of medicine and disease. This scroll was purchased in the 1800's by Georg Ebers, who found it in Thebes. The scroll is 20 meters long and is thought to be a compilation of much earlier texts.

Greece

460 BC – 370 BC Alexandria

Hippocrates developed the humoral theory of the nature of disease and separated the discipline of medicine from religion by claiming that disease was the product of environmental factors, diet, and living habits rather than a punishment inflicted by the gods. It also appears that animal dissection may have moved from death preparation to investigation at this time. The Sacred Disease, one treatise of the Hippocratic Corpus, describes dissections of animals, apparently for the explicit purpose of drawing comparisons with human conditions. Excerpt: The brain of man, as in all other animals, is double, and a thin membrane divides it through the middle, and therefore the pain is not always in the same part of the head; for sometimes it is situated on either side, and sometimes the whole is affected. (*Scroll down and see work on this concept continuing in 1981.) Thus this period appears to be the first clear move toward the field of comparative medicine. It is generally believed that the greeks did not practice postmortem examination of humans, so in text such as On Ancient Medicine human internal organs are described as they can be seen or felt externally. Hippocrates did advocate, and likely practiced surgical intervention, however, including trephining the skull, and described cautious blood letting for some conditions. He is also attributed with the first use of the term apoptosis.

384 BC – 322 BC
Aristotle (considered as one the founders of zoology) - Identified the heart as the center of intellectual reason.

335 BC – 280 BC Herophilos and
304 BC – 250 BC Erasistratos

Both dissected bodies of the dead, and performed vivisection on living criminals (as part of the punishment). Herophilos is believed to be among the first to pursue anatomy as a science, and identifying correlates between structure and disease. Erasistratos, through extensive dissection, identified the nervous system as the center of intellect, challenging Aristotle's convictions. He generated a number of correlates between clinical symptoms and observed morphological change. The work of both also contradicted the established Hippocratic theory.

In truth, the understanding of anatomy and physiology and correlations with disease did not proceed in anything like a linear fashion. Understanding how the pumping of the heart related to the circulatory system, for instance, likely had a great deal of ebb and flow as Greek culture mixed with Egyptian practices and later as Roman influences intermixed. Click on the image below to read a fantastic introduction to a translated papyrus focused on surgical procedures. The author's introduction does a great job describing this period of development. (Thank you University of Chicago Oriental Institute on-line archives!)

Rome

30 BC–38 AD - Cornelius Celsus - early Roman medical writer and author of De Re Medicina in eight volumes. Book III contains the cardinal signs of classic inflammation: “Notae vero inflammationis sunt quatuor, rubor et tumor, cum calore et dolore”. During this time human dissection was illegal in Rome.

Asia Minor.

129 AD – 201 AD - Galen. Born in Pergamus. As a physician he was offered Roman citizenship, brining Greek concepts, including the Hippocratic theory of the four humours, to Rome. Galen had a broader view of medicine than some Greek predecessors and likely conducted dissections of animals (pigs, monkeys), from which he identified the structure and function of the recurrent nerve and the urinary system. He developed the 'doctrine of laudable pus’, described the ‘crab-like’ growth of cancer, and introduced bloodletting. Although dispute continues, he is variously attributed to adding a ‘fifth sign of inflammation’, either ‘loss of function’, or throbbing/pulsation. Galen’s views on pathology were recording in some of his estimated 500-600 books, including “Seats of Diseases” and “Abnormal Tumours”.

502 AD – 575 AD Aetius of Amida – Mesopotamia

Trained in Alexandria and appointed as the physician to the emperor Justinian, he wrote 16 books on medical practice that included descriptions of numerous disease conditions. The fourth and fifth books take up hygiene, special dietetics, and general pathology. Topics in special pathology begin with the 6th book, covering diseases of the head. In this book treatments for hydrocephalus and rabies are described. Other conditions covered in the books include carcinoma of the uterus, hemorrhoids, condylomata, fissures and ulcers of the rectum. He is said to have treated breast cancer by amputation and cautery

1070 AD – 1162 AD Avenzoar – Seville, Spain; A Jewish physician who described cancer of the esophagus and the stomach, in addition to other lesions, invented the cannula, excised skin cancers, and performed hysterectomy.

Italy

Interest in medicine was rekindled in Italian universities, where investigation of anatomy and pathology in medical faculties developed in the mid-late 1200s; Faculties in Bologna practised human dissections as regular part of the medical anatomy teaching, pathologic study, and to investigate legal aspects of death - perhaps the first developments toward forensic pathology. Through the
1300-1400s dissections became increasingly common, mostly attempting to substantiate the theories of Galen.

1443 AD – 1502 AD - Antonio Benivieni - A Florentine physician, he recorded case histories and performed autopsies on some of his patients. After his death, 111 cases, among which were 20 post-mortems, were published in: “De Abditis Nonnullis ac Mirandis Morborum et Sanationum Causis” (About the Hidden Causes of Disease).

1476 AD - 1553 AD – Girolamo Francastoro, also an italian physician, worked on the concept of contagion and seeds of disease – he coined the name ‘syphilis’ in a poem he wrote in 1530, and identified rabies, measles and scabies.

High Middle ages -
Crusades 1096 AD - 1289 AD

In the face of plague that reached Italy in 1347 from the Middle East by sailors and that came to England by 1348, monks in monasteries took on roles previously held by physicians, and they copied, translated, and maintained Greek and later medical text. 1/3 to 1/2 of the European population died during this period.

Late 1400's-early 1700s - European developments

1497 AD – 1558 AD Jean Fernel - After a career in mathematics and astrology became focused on pathology, producing “Medicina” (one part called Pathologiae Libri). In this he classified diseases as general and special ones, and distinguished symptoms and signs, a system generally adhered to today. He diagnosed at autopsy a case of acute appendicitis, and was one of the first to suggest the syphilitic origin of some aneurysms.

1536 AD – 1614 AD Swiss anatomist Felix Plater who described an intracranial tumor, developed descriptions of psychiatric diseases, and described the correct anatomic underpinnings of Dupuytren's disease.

1530 AD – 1598 AD German physician Johann Schenk von Graftenberg studied the relationship between brain anatomy and linguistics.

1534 AD – 1576 AD the Dutch anatomist Volcher Coiter developed comparative osteology, described cerebrospinal meningitis, contibuted to the feilds of embryology and ornithology. Photo credit: http://nyamcenterforhistory.org/2013/10/03/a-renaissance-man-at-work-volcher-coiters-externarum-et-internarum-principalium-humani-corporis-of-1573-guest-post-by-morbid-anatomy/

1578 AD – 1657 AD William Harvey The publication of “De Motu Cordis et Sanguinis”, in 1628, revolutionised medicine and concepts of disease causation. The realisation of the circulation of blood and the function of the heart was a severe blow for the humoral theory, one that would eventually lead to its demise. Harvey also made important observations on the pathologic heart: ventricular rupture and left-sided hypertrophy in a patient with aortic valve insufficiency.

1580 AD – 1656 AD seventeenth century, surgeon Marco Aurelio Severino the first illustrations of disease processes or pathologic changes.

1593 AD – 1674 AD Anatomical paintings and drawings by the Nicolaas Tulp

1620 AD – 1689 AD Theophile Bonet - 1679 “Sepulchretum sive Anatomica Practica” published - collected case descriptions of autopsies from the last two centuries, and then added cases of his own. The two 1,700- page volumes contain a remarkable 3,000 autopsy reports, arranged in anatomical sections “from head to toe”, with comments and references.

1640 AD – 1693 AD Theodore Kerkring - Dutch anatomist who published “Spicilegium Anatomicum”.

1650 AD – AD 1702 Steven Blankaart “Anatomica Practica” of These first texts of pathological anatomy were available to the medical profession at the beginning of the eighteenth century

1666 AD – 1723 AD - Antonio Valsalva
1668–1738 Herman Boerhaave made a substantial contribution by publishing autopsy cases that related to, and clearly explained, the recent medical history of patients

1676 – Thomas Sydenham – claimed that the commonality of disease symptoms are so uniform that doctors should be able to classify them in the way botanists classify plants.

Early 1700s - early 1900s - European developments

1682–1771 - Giovanni Batista Morgagni, a medical student in Bologna. 1706, at the age of 24 years, Morgagni gained instant fame with his first important book, “Adversaria Anatomica”, followed in the next years by five other volumes. His opus magnum, “De Sedibus et Causis Morborum per Anatomen Indagatis” (about the seats and causes of diseases through anatomical investigation), was only published in 1761 when he was 79 years old (Fig. 5). In 70 letters to an unknown friend, Morgagni described here 640 autopsies, structurally correlating the symptoms of his patients with the pathological findings at autopsy, fostering the growing belief that diseases had an anatomical substrate.

Morgagni established the concept that diseases were organ based.

1728–1793 John Hunter - Beginning about 1750, and initially working with his brother William Hunter, John Hunter was author of numerous papers to the Royal Society on exceedingly diverse topics that might be described as experimental pathology, including the use of primitive microscopes. He also was author of “Venereal Disease” (1786) and of “Treatise on the Blood, Inflammation and Gunshot Wounds”, which was published by his executors in 1794. Hunter described inflammation, regarding it first as a defensive mechanism, and second as a reparative process. Hunter himself died of a heart attack following a heated discussion about the admission of students at St. George’s, his hospital. The Hunterian Museum at the Royal College of Surgeons in London stands as a silent witness of his enormous achievements. Remarkably, his nephew Mathew Baillie (1761–1823), who worked and trained with both John and William Hunter, extended their legacy, as well as his own, continuing the museum and expanding the teaching of morbid anatomy. Baillie is credited with not only perhaps the first systematic textbook of pathology, “The Morbid Anatomy of Some of the Most Important Parts of the Human Body” (1793), but also a series of beautiful copper engravings that coordinated with the text

Marie Francois Xavier Bichat used his connections as army surgeon during the French Revolution to obtain permission to investigate the fresh bodies of those who were guillotined. By simple methods (e.g., cooking), without use of the microscope, he was able to identify 21 types of tissues, improving the foundation for tissue-based disease. In his autopsies, he correlated the clinical findings with “histology”, a term that really gained currency 50 years later. He died at the age of 31 in 1802 of tuberculosis

Bichat Marie-François-Xavier. French. The first to describe tissues as distinct entities attacked by disease. He was author of “Anatomie générale, appliquée à la physiologie et à la médecine” (Paris, 1847).

1798–1866 – British. Thomas Hodgkin (portrait left) a general physician with a broad range of interests was one of the first to pursue the lead of Bichat, describing the pathological changes in tissues. In his twin papers, On Some Morbid Appearances of the Absorbent Glands and the Spleen (1832), he records his findings in seven autopsies, including recognisable cases of tuberculosis and also the disease that, 30 years later was, by Samuel Wilkes, given his name. Hodgkin had earlier published with Lister (father of Joseph Lister of antisepsis fame) a paper using the microscope, but notably did not employ it in his more famous 1832 publication. However, in publishing two volumes of his “Lectures on Pathologic Anatomy” in 1836 and 1840, Hodgkin did catch a glimpse of the new pathology: “Lister’s compound microscope might lead to useful discoveries in the future”.

1789–1858 Richard Bright. English physician who pioneered studies in renal disease is known as the father of nephrology and investigated the origins of stroke, linking the condition to vascular obstruction.

1793–1860 Thomas Addison Bright is famous for his extensive studies about the relation between kidney disease and oedema and for his recognition of pernicious anaemia.

1804–1878 Carl von Rokitansky - considered disease states to result from anomalies of the blood, inducing still more blood anomalies. He firmly believed that chemical pathologists eventually might resolve many of the unknowns in pathology. Von Rokitansky’s publication of his convictions caused Rudolf Virchow to react, calling this “humoral theory” a “monstrous anachronism”, despite his persisting admiration for Von Rokitansky as a great descriptive pathologist

1813-1858 – John Snow – Researched Cholera epidemic in London, concluding to was feces contaminated water rather than miasma involved in its transmission.

1822-1895 – Louis Pasteur – Developed the Germ theory of disease

1821–1902 Rudolf Virchow - Came to use the microscope routinely in his autopsy studies. He likely provided the first description of apoptotic cell death, though the term first appears in ancient Greek descriptions.

1801–1858 - Johannes Müller in Berlin. A case can be made that Müller was the source from which both histology and cellular pathology arose. He was one of the first to use the microscope in tissue analysis. As early as 1830, he had made extensive studies of different tissues, resulting in a book “Ueber den feinern Bau und die Formen der krankhaften Geschwülste” (On the Finer Structure and Form of Morbid Tumors), which appeared in 1838.

Schwann, another student of Müller, first pointed to cellular growth as the basic principle of animal life, a thesis that established for all time the cellular character of all growth. Only one step remained, the recognition of continuity of cellular life, a step that Virchow took, as expressed in his immortal aphorism “Omnis cellula e cellula”.

1849 – William Osler – Canadian physician who wrote “The relation of Animals to Man”, helped for the modern concept of comparative pathology, and documented the causes of several animal diseases, including “verminous bronchitis” - the pulmonary nematode still bears his name: Filaroides osleri, hog cholera, and several types of tape worm infection

1850 diagnostic histopathology became more and more important, especially in the area of neoplasia, and this stimulated the development of pathology as a separate “specialty”.

In France pathology was mainly practiced in laboratories in Paris, while in Germany pathology was the sum of a score of busy, productive universities. Britain was somewhere in between.

1843-1910 – Robert Koch – Physician who identified the lifecycle of anthrax, and identified the causal organisms of tuberculosis and cholera (1905 Nobel prize for his investigations and discoveries in relation to tuberculosis)

1834–1913 - Edwin Klebs introduced paraffin embedding in 1869
and developed the embedding process through hardening and dehydration using acetic acid and Zenker’s fluid. Student of Virchow, forged links between bacteriology and infectious disease. His investigations on the infectious nature of endocarditis (1878) illustrate the direction of his work. Through his discoveries, Klebs moved away from the ideas of his mentor Virchow, in that he considered etiology as the first priority in the study of disease and relegated pathological anatomy to a secondary place

1893 Isaac Blum (1833–1903) and son Ferdinand Blum (1865–1959) Formaldehyde solution became the most used fixative.

1865 - Franz Böhmer from Würzburg published the use of alum hematoxylin as a nuclear stain.

1839–1884 - Julius Cohnheim who broke with the traditional beliefs as to the origin of the ‘pus’ cell; he clearly demonstrated that they came from the blood and were not local tissue cells, as presumed by Virchow.

1845–1904 - Carl Weigert extended these observations to provide new understanding of the mechanisms of degeneration and necrosis.

1854–1915 - Paul Ehrlich - Discovery and use of aniline dyes the repertoire of stains available expanded rapidly, generating a new literature based upon descriptions of diseases defined by their microscopic features.

1833–1910 - Friedrich von Recklinghausen distinguished pupil of Virchow, he was both an able experimental pathologist and a practising anatomic pathologist. Although mostly remembered for his description of ‘multiple neurofibromatosis’, this discovery was relatively minor for he left his mark in almost every field of pathology. Von Recklinghausen was a masterly investigator of bone pathology, both the primary and the secondary bone growths. He published important studies on thrombosis, embolism, infarction, degenerations, hemochromatosis, adenomyomata of the uterus, and other many other pathologic conditions.

Early 1900’s
In the late 1800's Ronald Ross, a British citizen living and working in India as a practitioner of public health, discovered, following a tip from Patrick Manson, malarial parasites within mosquitoes and in 1902 he received a Nobel prize for his work showing how malaria enters its host.

1866–1942 - Ludwig Aschoff who developed the concept of the reticulo-endothelial system

1885–1964 - Russian pathologist Nikolai Anitschkov described the histopathology of the heart for a number of diseases including rheumatic fever and proposed the role of cholesterol in atherosclerosis.

Franz Volkard and Theodor Fahr - New understanding of kidney diseases

1884–1964 - Paul Klemperer introduced the concept of “collagen disease” (1942).

1868–1943 - Pathologist Karl Landsteiner performed more than 3,600 autopsies during his training. He established a basis for modern blood typing (1901), helping to set the stage for development of blood transfusion, and eventually tissue transplantation.

1906 - The Nobel Prize in Physiology or Medicine was awarded to histologists Camillo Golgi and Santiago Ramon y Cajal. They had dueling interpretations of the neural structure of the brain based on differing interpretations of the same images. Cajal won the prize for his correct theory and Golgi for the staining technique he invented to make it possible.

Sir Ronald Ross, Mrs. Ross, Mahomed Bux and laboratory assistants at the laboratory in Calcutta where the life history of the malaria parasite in birds was fully worked out in 1898. (Photo credit: London School of Hygiene and Tropical Medicine)

Anitschkow cell on H&E section - a cell sometimes referred to as a caterpillar cell because of it's wavy nucleus. These are found in the myocardium, particularly in some disease states such as rheumatic fever. They are thought to be macrophages or attempts at myofiber regeneration.

Drawing of a section through the optic tectum of a sparrow, from: Ramón y Cajal, S., "Estructura de los centros nerviosos de las aves", Madrid, 1905. Image from https://wiki.brown.edu/confluence/
display/BN0193S04/Neuron+Doctrine

1909 Emil Theodor Kocher receiver a Nobel Prize for his work on the physiology, pathology and surgery of the thyroid gland.

1926 - Johannes Andreas Grib Fibiger was a Danish student of Koch. As a physician and anatomic pathologist he received the Nobel prize for his discovery of Spiroptera (Gongylonema neoplasticum) induced carcinoma. Interestingly, in 1809, Spirocera lupi was described in the esophagus of dogs by Rudolphi and was later associated with inducing several tumors.

1936 - Sir Henry Hallett Dale and Otto Loewi received the Nobel prize in 1936 for their discoveries relating to chemical transmission of nerve impulses.

1912–1978 - Albert Coons - An American physician, pathologist and immunologist who developed (with Louis Fieser) fluorescein-labelled antibodies in the early 1940s.

1927–2002 César Milstein - Argentinian molecular biologist. In 1975 he, with Georges Kohler, developed monoclonal antibodies at Cambridge in, interestingly, the same lab where Watson and Crick discovered the structure of DNA about 20 years prior.

Mid 21st Century to now Nobel prize winners in Physiology or Medicine

1943 - Henrik Carl Peter Dam for his discovery of vitamin K

1944 - PCR polymerase chain reaction by Kary Mullis

1944 Joseph Erlanger and Herbert Spencer Gasser for their discoveries relating to the highly differentiated functions of single nerve fibres.

1945 Sir Alexander Fleming, Ernst Boris Chain and Sir Howard Walter Florey for the discovery of penicillin and its curative effect in various infectious diseases.

1946–1995 Georges Köhler the immune system production of monoclonal antibodies.

1946 Hermann Joseph Muller for the discovery of the production of mutations by means of X-ray irradiation.

1951 - Max Theiler for his discoveries concerning yellow fever and how to combat it.

1954 John Franklin Enders, Thomas Huckle Weller and Frederick Chapman Robbin s for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue.

1966 Peyton Rous for his discovery of tumour-inducing viruses.

1972 - John F. Kerr re-defined apoptosis based on discovery of apoptotic mechanisms.

1974 Albert Claude, Christian de Duve and George E. Palade for their discoveries concerning the structural and functional organization of the cell.

1976 Baruch S. Blumberg and D. Carleton Gajdusek for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases.

1979 Allan M. Cormack and Godfrey N. Hounsfield for the development of computer assisted tomography.

1981 Roger W. Sperry for his discoveries concerning the functional specialization of the cerebral hemispheres.

1997 Stanley B. Prusiner for his discovery of Prions - a new biological principle of infection.

1998 Robert F. Furchgott, Louis J. Ignarro and Ferid Murad for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system.

2000 Arvid Carlsson, Paul Greengard and Eric R. Kandel for their discoveries concerning signal transduction in the nervous system.

2002 Sydney Brenner, H. Robert Horvitz and John E. Sulston for their discoveries concerning genetic regulation of organ development and programmed cell death.

2003 Paul C. Lauterbur and Sir Peter Mansfield for their discoveries concerning magnetic resonance imaging.

2004 Richard Axel and Linda B. Buck for their discoveries of odorant receptors and the organization of the olfactory system.

2005 J. Marshall and J. Robin Warren for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease.

2008 Harald zur Hausen Barry for his discovery of human papilloma viruses causing cervical cancer.

2008 Françoise Barré-Sinoussi and Luc Montagnier for their discovery of human immunodeficiency virus.

2013 James E. Rothman, Randy W. Schekman and Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.