A Brief History of Pathology PDF

Virchows Arch (2010) 457:3–10 DOI 10.1007/s00428-010-0934-4 INVITED EDITORIAL A brief history of pathology Preface to a forthcoming series that highlights milestones in the evolution of pathology as a discipline Jan G. van den Tweel & Clive R. Taylor Received: 21 April 2010 / Accepted: 6 May 20...

Virchows Arch (2010) 457:3–10 DOI 10.1007/s00428-010-0934-4 INVITED EDITORIAL A brief history of pathology Preface to a forthcoming series that highlights milestones in the evolution of pathology as a discipline Jan G. van den Tweel & Clive R. Taylor Received: 21 April 2010 / Accepted: 6 May 2010 / Published online: 25 May 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com “It is a poor sort of memory that only works backwards”. hernias, breast tumours, varicose veins, ulcers and other diseases. The Queen to Alice in ‘Through the Looking Glass’. Documentation of disease really begins with Egyptian Lewis Carol. Ch 5; Wool and Water. medicine, where the most important sources are the Edwin Smith Papyrus (17th century BC) and Papyrus Ebers (about 1550 BC). These records contain information on different There is no single event, no ‘Big Bang’, that demarcates types of bone injuries, trachoma (Nile valley), ulcerating the beginning of pathology as a defined area of interest for lumps (cancer?), parasites and other diseases. However, early medical practitioners. In fact, the history of pathology despite the many thousands of ritualistic and painstaking has roots in common with all other medical specialties, embalmings during nearly 5,000 years of successive arising in antiquity when men reasoned about the physical Egyptian dynasties, these surviving papyri contain only a ailments that afflicted them. For obvious reasons, those slender body of information on pathological anatomy. gross features of disease that were directly visible, either in Today, we know from recent investigations of mummies life, or after death in funereal preparations, came first to that bone tumours and tuberculosis of the spine occurred in notice. In addition, over the last century, archaeological Ancient Egypt, as well as atherosclerosis, gallstones and discoveries increasingly have been linked with palaeopa- abscesses, yet there is little evidence that the Egyptians thological investigations, furnishing a wealth of observa- developed any systematic knowledge of these phenomena. tions of gross external features of disease, from prehistoric It was not until the last three centuries BC that the peoples to the present time. As a result, museums around Alexandrian Greeks, heavily influenced by Hippocrates, the world contain marble and terra cotta statues expressing made lasting contributions to anatomy and pathology processes that can now be interpreted as examples of The ideas related to Hippocrates of Cos (460–370? BC) and his school had an enormous impact on Greek and Roman medicine. With his humoural theory of the nature of J. G. van den Tweel (*) disease, Hippocrates influenced medicine until the Renais- Department of Pathology H4.312, University Medical Center, sance, and beyond. Despite the flaws of this theory, Heidelberglaan 100, Hippocratic writers left remarkably clear descriptions of 3584 CX Utrecht, The Netherlands many pathological features, such as wound inflammation, e-mail: [email protected] tumours, haemorrhoids, malaria and tuberculosis (Fig. 1). C. R. Taylor (*) Animal dissection was practised in this time, but human Department of Pathology, HMR 311, Keck School dissection was not part of medical practice. Similar of Medicine of the University of Southern California, circumstances apply to Aristotle (384–322), who can be 2011 Zonal Avenue, Los Angeles, CA 90033, USA considered as one the founders of zoology. The first e-mail: [email protected] dissections of humans are attributed to the Alexandrian 4 Virchows Arch (2010) 457:3–10 in decline, the advances of the Alexandrian School were largely neglected, in spite of the fact that Celsus had compiled the major elements in a concise form. The leading Asiatic Greek physicians were also little inclined to test their speculations openly. Human dissections ceased to performed, being unlawful in Rome, and medical practice entered the doldrums for a hundred years. Fortunately, the second century gave us a literal giant, Galen (129– 201 AD). Born in Pergamus, Asia Minor, he is by many considered as the greatest medical figure of that time and maybe of all time. He followed the Greek concepts, including the Hippocratic theory of the four humours, but broadened his education and views by extensive travel, including time spent at the great school in Alexandria (Fig. 2). By (vivi)dissection of animals (pigs, monkeys), he realised the importance of such structures as the recurrent Fig. 1 Hippocrates: a page from “Aphorismi, sive, Sententiae” In: Hunayn ibn-Ishaq al-'Ibadi, Oxford, XIIIth century. Courtesy National nerve and the urinary system. He described the ‘crab-like’ Library of Medicin, Bethesda, USA 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 scientists Herophilos (335–280 BC) and Erasistratos (304– throbbing/pulsation. Galen’s views on pathology are found 250). Unfortunately, their writings are all lost, and we know in his books “Seats of Diseases” and “Abnormal Tumours”. of their work only second hand. The Roman writers Celsus His prodigious writings have been estimated as between and Tertullian stated that the Alexandrians not only 500 and 600 books and treatises. Although only about one dissected bodies of the dead, but also performed vivisection third of these survived, his writings directed medicine for on living criminals (as part of the punishment). Herophilos over a thousand years, into the Middle Ages. Unfortunately, is believed to be among the first to pursue anatomy as a uncritical acceptance of Galen’s views over this period science, constantly trying to correlate structure with resulted in the same long period of unproductive medical disease, while his contemporary, Erasistratos, was more a thinking. physiologist than an anatomist. Although lacking sound Pathology in the period between Galen and the late anatomical and physiological knowledge, they nonetheless Middle Ages, was mainly influenced by Byzantine and sought to explain symptoms and complaints by reference to Arab physicians, although little significant change resulted. observed morphological changes. Both these men and their Among the former is Aetius of Amida (502–575), physician followers broke with the established Hippocratic theory. to the emperor Justinian, who left excellent descriptions of However, they were unable to introduce any new doctrine in its place, and their impact was short lived. Long before the destruction of the famous Alexandrian library in 48 BC, Hippocratic ‘science’ was again pre-eminent. With the end of the Hellenistic era, many elements of Greek culture and medicine survived and were exported to newly emerging Rome. The early Roman practitioners of medicine either came from Greece or had received training in the Greek method. The most important early Roman medical writer was unquestionably Cornelius Celsus (about 30BC–38 AD). He was apparently not a physician, but an educated man with an extensive knowledge of literature. He wrote De Re Medicina in eight volumes. Book III contains the classic definition of inflammation: “Notae vero inflammationis sunt quatuor, rubor et tumor, cum calore et dolore”, until now learned by every medical student. Fig. 2 Hippocrates and Galen accompanied by John Hunter in this The first century AD held few new developments. statue at the campus of the USC Medical Center, Los Angeles Country Although the humoural concept of disease was temporarily Hospital, Los Angeles, USA. Sculptor: Salvatore Scarpitta, 1934 Virchows Arch (2010) 457:3–10 5 carcinoma of the uterus, and of haemorrhoids, condylomata, Galen. It would be another 200 years before abandonment fissures and ulcers (cancers?) of the rectum. One of the of the humoral theory swept away cherished misconcep- greatest writers of the Arab period was Avicenna (980– tions and opened the way to seeing with new eyes and open 1037), an illustrious physician whose major work the minds correlations between symptoms and the underlying “Canon Medicinae” was based on the doctrines of Galen disease. and Aristotle, and remained until the fifteenth century the If there is a moment when it might be claimed that best single work in medicine (Fig. 3). A century later he Pathology took wing as a separate specialty then it is to be was succeeded by Avenzoar (1070–1162), who described found at the end of the fifteenth century, in the work of the cancer of the oesophagus and the stomach quite accurately, Florentine physician, Antonio Benivieni (1443–1502), who in addition to other lesions. However, these individual recorded case histories and performed autopsies on some of descriptions notwithstanding, the Byzantine and the Arab his patients. After his death, 111 cases, among which were school did little to advance overall understanding of 20 post-mortems, were published in a little classic: “De disease. With the decline of Arab medicine after the Abditis Nonnullis ac Mirandis Morborum et Sanationum crusades, monasteries across Europe were the places where Causis” (About the Hidden Causes of Disease). The stage the tenets of Greek medicine were kept alive. Monks had been set and the sixteenth century then gave us several effectively became physicians or occupied themselves with brilliant and renowned anatomists, who were increasingly copying and annotating ancient manuscripts, including aware of the pathological structures that they encountered those with medical connotations. The first indications of a during anatomical studies and whose names still are still revival of interest in medical knowledge coincided with the used in daily pathology practise (Fig. 4). While observa- foundation of the Italian universities, having medical tions of these abnormal features steadily accumulated, faculties who displayed renewed interest in anatomy and residual Hippocratic and Galenic influences hindered pathological anatomy. According to manuscripts from the progress. Vesalius (1514–1564), who was not a keen early fourteenth century, Bologna practised human dissec- follower of Galen, intended, according to a German tions as early as 1270 AD as regular part of the medical contemporary, to publish his pathological observations as teaching for the study of anatomy, but also to study disease a separate work; however, if completed, this work has never and legal aspects of death. Throughout the fourteenth and been found. fifteenth centuries, dissections became increasingly com- mon, mostly attempting to substantiate the theories of Fig. 3 Avicenna, Canon Medicinae, 14th century. Courtesy of the Fig. 4 Title page of Fallopius’ book: Opera Genuina Omnia. National Library of Medicine, Bethesda, USA Courtesy of the National Library of Medicine, Bethesda, USA 6 Virchows Arch (2010) 457:3–10 The first to attempt formally to codify this developing pathologic observations were published in textbooks and new knowledge was Jean Fernel (1497–1558), who after a journals. Herman Boerhaave (1668–1738) made a substan- career in mathematics and astrology might in some ways be tial contribution by publishing autopsy cases that related to, regarded as a full-fledged pathologist. His main work and clearly explained, the recent medical history of patients. “Medicina” (one part called Pathologiae Libri), became Many followed; however, the one man with the vision to standard throughout Europe. He classified diseases as break with 1,500 years of Galen’s influence was Giovanni general and special ones, and distinguished symptoms and Batista Morgagni (1682–1771), a medical student in signs, much as we do today. He diagnosed at autopsy a case Bologna, and student of the great anatomist Antonio of acute appendicitis, and was one of the first to suggest the Valsalva (1666–1723). In 1706, at the age of 24 years, syphilitic origin of some aneurysms. Important successors Morgagni gained instant fame with his first important book, included the Swiss anatomist Felix Plater (1536–1614), the “Adversaria Anatomica”, followed in the next years by five Dutch anatomist Volcher Coiter (1534–1576), and the other volumes. His opus magnum, “De Sedibus et Causis German, Johann Schenk von Graftenberg (1530–1598). In Morborum per Anatomen Indagatis” (about the seats and retrospect it seems amazing that, in spite of the detailed causes of diseases through anatomical investigation), was work of all these anatomists, the balance of belief remained only published in 1761 when he was 79 years old (Fig. 5). still with Galen, so deeply were these now ancient In 70 letters to an unknown friend, Morgagni described teachings embedded in the learning and practice of here 640 autopsies, structurally correlating the symptoms of medicine. his patients with the pathological findings at autopsy, The new dawn began only with William Harvey (1578– fostering the growing belief that diseases had an anatomical 1657).The publication of “De Motu Cordis et Sanguinis”, substrate. in 1628, revolutionised medicine and concepts of disease Morgagni was the highpoint of a tradition that had causation. The realisation of the circulation of blood and progressed steadily since the sixteenth century, and his the function of the heart was a severe blow for the humoral work was the beginning of modern medicine and pathology. theory, one that would eventually lead to its demise. Harvey It became generally accepted that diseases were organ also made important observations on the pathologic heart: based. Many others (had) added to this growing body of ventricular rupture and left-sided hypertrophy in a patient knowledge. John Hunter (1728–1793) was not just one of with aortic valve insufficiency. In the seventeenth century, them; he was an extraordinary one. Beginning about 1750, we see also the first illustrations of disease processes or and initially working with his brother William Hunter, John pathologic changes. An early example is the drawings by Hunter was author of numerous papers to the Royal Society the surgeon Marco Aurelio Severino (1580–1656), fol- on exceedingly diverse topics that might be described as lowed by those of Nicolaas Tulp (1593–1674). Many other experimental pathology, including the use of primitive physicians studied diseases at autopsy, and some collected microscopes. He also was author of “Venereal Disease” and published their findings as ‘specilegia’, assemblages of (1786) and of “Treatise on the Blood, Inflammation and autopsy reports. Of these the most important by far is Gunshot Wounds”, which was published by his executors in Bonet’s “Sepulchretum sive Anatomica Practica”, pub- 1794. Hunter described inflammation, regarding it first as a lished in 1679. In this work Theophile Bonet (1620–1689) defensive mechanism, and second as a reparative process. collected case descriptions of autopsies from the last two With him the ‘doctrine of laudable pus’ (Galen) died. centuries, and then added cases of his own. The two 1,700- Hunter himself died of a heart attack following a heated page volumes contain a remarkable 3,000 autopsy reports, discussion about the admission of students at St. George’s, arranged in anatomical sections “from head to toe”, with his hospital. The Hunterian Museum at the Royal College comments and references. Two other important compila- of Surgeons in London stands as a silent witness of his tions of that period were the “Spicilegium Anatomicum” by enormous achievements. Remarkably, his nephew Mathew Dutchman Theodore Kerkring (1640–1693) and the Baillie (1761–1823), who worked and trained with both “Anatomica Practica” of Steven Blankaart (1650–1702). John and William Hunter, extended their legacy, as well as These first texts of pathological anatomy were available to his own, continuing the museum and expanding the the medical profession at the beginning of the eighteenth teaching of morbid anatomy. Baillie is credited with not century, waiting, it seems, for somebody to put the only perhaps the first systematic textbook of pathology, observations that they contained into proper context. In “The Morbid Anatomy of Some of the Most Important Parts the relative scale of time, considering that Galen’s ideas of the Human Body” (1793), but also a series of beautiful endured for 1,500 years, they would not have to wait long. copper engravings that coordinated with the text. Eighteenth century medicine was more sophisticated. In the year that Morgagni died, Marie Francois Xavier Pathology, through an abundance of autopsies, played an Bichat was born (Fig. 6). He used his connections as army increasingly important role in this development. Many surgeon during the French Revolution to obtain permission Virchows Arch (2010) 457:3–10 7 Fig. 5 A picture of Morgani in his most famous book “De Sedibus et Causis Morborum”. Courtesy Bilbliotheca Gambalunga, Rimini, Italy to investigate the fresh bodies of those who were Anatomie Pathologique” in two volumes, the first on guillotined. By simple methods (e.g., cooking), without general pathology and the second on special pathology. use of the microscope, he was able to identify 21 types of In Britain, Thomas Hodgkin (1798–1866), a general tissues, improving the foundation for tissue-based disease. physician with a broad range of interests was one of the In his autopsies, he correlated the clinical findings with first to pursue the lead of Bichat, describing the patholog- “histology”, a term that really gained currency 50 years ical changes in tissues. In his twin papers, On Some Morbid later. He died at the age of 31 in 1802 of tuberculosis. His Appearances of the Absorbent Glands and the Spleen work was continued by another Frenchman, Gabriel Andral (1832), he records his findings in seven autopsies, (1797–1876) who published in 1828 his “Précis d’ 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”. British pathology was also strengthened by men as Richard Bright (1789–1858) and Thomas Addison (1793–1860). Bright is famous for his extensive studies about the relation between kidney disease and oedema and Addison for his recognition of pernicious anaemia. From the mid-nineteenth century onwards, rather than the work of any one individual, it was ‘new technology’ that shaped the future of pathology. With increased availability, improved optics and reduced cost the use of Fig. 6 Bichat, Marie-François-Xavier. Author of “Anatomie générale, the microscope grew exponentially. The time was ripe for appliquée à la physiologie et à la médecine” (Paris, 1847). Artist Vigneron. Courtesy of the National Library of Medicine, Bethesda, the next giant breakthrough; pathologists were invented in a USA guise still more or less recognisable today. 8 Virchows Arch (2010) 457:3–10 While the microscope was the driving force, it was not same year, Schwann, another student of Müller, first the only force propelling medicine forward. The first half of pointed to cellular growth as the basic principle of animal the nineteenth century also witnessed a concurrent upsurge life, a thesis that established for all time the cellular of interest in the basic sciences, particularly physiology and character of all growth. Only one step remained, the chemistry, leading to a more scientific approach to the recognition of continuity of cellular life, a step that Virchow study of disease. This new scrutiny gave rise to a lot of new took, as expressed in his immortal aphorism “Omnis cellula questions. Fortuitously, at the same time, there were new e cellula”. Virchow’s training as a student with deep scientific methods available to answer them. The role of interest in the basic concepts of science was followed by microscopy in pathology became evident in a kind of the same interest and devotion for his work as an competition between Carl von Rokitansky (1804–1878) and (experimental) pathologist. His new insights resulted in a his one-time pupil Rudolf Virchow (1821–1902). The latter collection of twenty of his lectures into his most important came to use the microscope routinely in his autopsy studies, work “Die Cellularpathologie” (Berlin, 1858), translated to whereas his mentor, Von Rokitansky did so less frequently, English by Frank Chance in Cambridge in 1860. This sometimes resulting in theoretical interpretations that were remarkable book was a harbinger of what was to come, the not in accord with the new evidence of the day. Von next step in understanding, from organ-based disease to Rokitansky considered disease states to result from anoma- cell-based disease, the beginning of a ‘new pathology’. lies of the blood, inducing still more blood anomalies. He With the emergence of microscopy and the ground firmly believed that chemical pathologists eventually breaking work of Morgagni, Bichat and Virchow, the might resolve many of the unknowns in pathology. Von specialty of pathology entered a new era in the second half Rokitansky’s publication of his convictions caused Rudolf of the nineteenth century. In medical schools throughout Virchow to react, calling this “humoral theory” a Europe, ‘Inspectors of the Dead’ and ‘Curators of Museums’ “monstrous anachronism”, despite his persisting admira- began to be replaced by Lecturers in Morbid Anatomy, tion for Von Rokitansky as a great descriptive pathologist. then by Professors of Pathology. Many of these new Virchow (Fig. 7), by many regarded as the greatest professors promptly used the opportunity to claim their figure in the history of pathology, was a student of own department or building, setting an example that we Johannes Müller (1801–1858) in Berlin. A case can be strive to emulate even today! Although the autopsy made that Müller was the source from which both histology originally was performed by many doctors, from 1850 and cellular pathology arose. He was one of the first to use diagnostic histopathology became more and more impor- the microscope in tissue analysis. As early as 1830, he had tant, especially in the area of neoplasia, and this made extensive studies of different tissues, resulting in a stimulated the development of pathology as a separate book “Ueber den feinern Bau und die Formen der “specialty”. Not all countries saw the necessity for these krankhaften Geschwülste” (On the Finer Structure and changes at the same time; witness the extraordinary Form of Morbid Tumors), which appeared in 1838. In this contrast between France and Germany. In France pathology was mainly practised in laboratories in Paris, while in Germany pathology was the sum of a score of busy, productive universities. Britain was somewhere in between. There were the three generations of Monros in Edinburgh, plus the emergence of the London teaching hospitals, but it was some time before other schools appointed pathologists to chair a separate department. The microscope totally changed concepts of disease from whole organs, to focus upon cells; it enabled the practice of histopathology and spawned numerous attendant advances in technique necessary for modern practice. Thus in the beginning slices of fresh tissue were cut by hand and examined unstained. By contrast in the last decades of the century this crude approach had given way to fixed tissues, embedding techniques, microtomes, a plethora of biological stains, and greatly improved microscopes. The man who introduced paraf- Fig. 7 Portret of Rudolph L.K. Virchow (1821–1902). Courtesy of fin embedding in 1869 was Edwin Klebs (1834–1913). the National Library of Medicine, Bethesda, USA, undated (approx- To improve the embedding process, hardening and dehydra- imately 1865) tion were necessary. Chromic acid (1844), chrom-osmium- Virchows Arch (2010) 457:3–10 9 acetic acid and Zenker’s fluid entered routine use for this fever for example, and proposed the role of cholesterol in purpose. Formaldehyde solution was first advocated in 1893 atherosclerosis. New understanding of kidney diseases by Isaac Blum (1833–1903) and his son Ferdinand Blum stemmed from the work of Franz Volkard and Theodor (1865–1959) and from that moment, until today, became Fahr, while Paul Klemperer (1884–1964) introduced the the most used fixative. In 1865, Franz Böhmer from concept of “collagen disease” (1942). The research of Würzburg published the use of alum haematoxylin as a the pathologist Karl Landsteiner (1868–1943, he per- nuclear stain. With the discovery and use of aniline dyes formed more than 3,600 autopsies during his training!), by Paul Ehrlich (1854–1915) the repertoire of stains who provided the basis for modern blood typing (1901), available expanded rapidly, generating a new literature had even greater implication, leading in turn to new based upon descriptions of diseases defined by their fields of blood transfusion, and eventually tissue microscopic features. transplantation. Friedrich von Recklinghausen (1833–1910) was first From early days of the twentieth century to the present the among a group of pathologist who dominated the last pace of discovery and change has accelerated still more. decades of the nineteenth century. Probably the most Ongoing advances in the fields of fixation, embedding, distinguished pupil of Virchow, he was both an able cutting, immunohistochemical staining, molecular methods, experimental pathologist and a practising anatomic pathol- microscopy, and image processing have continued to yield ogist. Although mostly remembered for his description of better diagnostic tools, and new, better, more precise ‘multiple neurofibromatosis’, this discovery was relatively diagnoses. Many new journals have appeared to report these minor for he left his mark in almost every field of findings, including sub-specialty journals covering the broad- pathology. Von Recklinghausen was a masterly investigator est reaches of pathology. Numerous new entities have been of bone pathology, both the primary and the secondary described, refined, classified, re-described, and re-classified, bone growths. He published important studies on thrombo- as new techniques provided new insights. The revolutionary sis, embolism, infarction, degenerations, hemochromatosis, discoveries of fluorescein-labelled antibodies by Albert Coons adenomyomata of the uterus, and other many other (1912–1978, Fig. 8), of monoclonal antibodies by Georges pathologic conditions. Virchows Archiv was full of new Köhler (1946–1995) and César Milstein (1927–2002), and of discoveries in his period. Edwin Klebs (1843–1913), the polymerase chain reaction by Kary Mullis (1944–) had another student of Virchow, forged links between bacteri- an enormous impact leading to whole sale redefinition of ology and infectious disease. His investigations on the many of the morphology-based disease classifications, infectious nature of endocarditis (1878) illustrate the exemplified in the successive different editions of the AFIP direction of his work. Through his discoveries, Klebs moved away from the ideas of his mentor Virchow, in that he considered aetiology as the first priority in the study of disease and relegated pathological anatomy to a secondary place. Another different view arose from the work of Julius Cohnheim (1839–1884), 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. Cohnheim’s distinguished pupil, Carl Weigert (1845–1904), extended these observations to provide new understanding of the mechanisms of degeneration and necrosis. As one enters the twentieth century, the pace of research in pathology palpably accelerated, the number of discoveries grew almost exponentially, and also the number of discoverers. At the turn of the century the Sternberg (1898)–Reed (1902) cell was born, and many basic features of histopathology were first recorded, exem- plifying the primacy of the microscope in pathologic research and diagnosis. The first half of twentieth century gave us, amongst others, Ludwig Aschoff (1866–1942), who developed the concept of the reticulo-endothelial system, and Nikolai Anitschkov (1885–1964), who Fig. 8 Albert Coons, discoverer of immunofluorescence techniques. described the histopathology of the heart, in rheumatic Courtesy of the Harvard Medical School Countway Library 10 Virchows Arch (2010) 457:3–10 tumour atlases and the WHO ‘blue books’. These discoveries occurred; time ultimately will reveal the new face of have shaped today’s pathology practise. pathology. Conclusion Open Access This article is distributed under the terms of the Over a span of 4,000 years, concepts of medicine and Creative Commons Attribution Noncommercial License which per- disease have changed, driven at times by remarkable men mits any noncommercial use, distribution, and reproduction in any and women, and more recently also by the relentless medium, provided the original author(s) and source are credited. progress of technology. In looking for the cause of disease, the earliest physicians embraced the entire body, and often also the gods and goddesses, the stars and the References heavenly bodies in their orbits. Then came the ‘four humours’ and other theories, holding physicians in thrall 1. Adler R (2004) Medical first. From hippocrates to the human genome. Wiley, Hoboken for almost 2,000 years, yielding only in the last few 2. 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