The history of pathology involves human dissections, autopsies, microscopy, as well as the development of histopathological, immunohistochemical, and molecular techniques. Through these methods, our understanding of anatomy and disease improved, and models of pathogenesis were gradually refined over time. This review discusses key milestones in the development of pathology as a branch of medical science, from ancient civilizations to the modern day.

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Introduction

Pathology in modern medicine is defined as the study of disease, and etymologically means “study of suffering” (Greek pathos = suffering, logos = study) [1]. Today, pathology is practised as a medical discipline that underpins many aspects of patient care, including diagnostic testing, prognostication, and advice on treatment modalities. This fundamentally involves the examination of material obtained from the human body such as bodily fluids (as with chemical pathology and microbiology), surgically resected organs (as with histopathology), or the human cadaver itself (as with forensic pathology). How did we realize that this was key to understanding disease? Who pioneered these diagnostic methods? In this article, we peer through the retrospective lens in the history of pathology and examine how this field developed.

Ancient Civilizations

The first recorded attempts of mankind at describing disease are found in a series of Egyptian medical papyri. Of these, two receive the greatest attention – the Ebers papyrus (c. 1500 BC), known for being the largest record of ancient Egyptian medicine at 68 feet long, and comprising a total of 811 pharmacological prescriptions [2], as well as the Edwin Smith papyrus (c. 1700 BC), which is considered the oldest known surgical text on wound treatment [3].

According to the Ebers papyrus, ancient Egyptians theorized that 22 vessels (also known as “mtw”) formed the basis of human physiology. The vessels were thought of as canals in which various substances flowed and opened to the external environment through natural bodily orifices. A separate religious concept of “maat” (balance, order, justice) guided their explanation for illness, whereby health required a balance of flow within the mtw-vessels, just like how their country depended on the regularity of the Nile flooding for crop irrigation [4]. Medicine and religion were closely intertwined, and a strict natural-supernatural dichotomy did not exist; while traumatic injuries or noxious substances could impede the flow within mtw-vessels and disrupt maat, it was believed that gods could do the same as a form of divine punishment [4]. A further example which illustrates this can be found in the Edwin Smith papyrus, which depicts the use of a magic charm and ostrich egg in treating a comminuted skull fracture [3].

While the concept of mtw-vessels is essentially proven untrue with modern scientific advancements, the Egyptians demonstrated a surprising level of anatomical knowledge on other fronts. This is perhaps best characterized by embalming procedures for the purpose of mummification, whereby brain tissue was removed via a transnasal route – a practice which required understanding of skull base anatomy. Yet, religious beliefs that the body had to be preserved in good condition for the afterlife likely meant that human dissection was not performed for academic studies [5].

Subsequent medical literature continues to describe religious and moral taboos as a barrier to human dissection – a theme which recurred cross-culturally. In ancient Greece, sacred laws considered the human corpse as a source of pollution; dying was prohibited on the grounds of a temple, and any person “contaminated” by a corpse was prohibited from visiting shrines for periods ranging from 2 to 41 days [6]. Similarly, the Chinese doctrines of Confucius (c. 551–479 BC) forbade violation of the body, and the Hindu religious laws of ancient India prohibited touching the deceased other than for purposes of cremation [7]. In parallel fashion, disease was ascribed to causes without an anatomical/organ-centric basis; these included theories such as humorism (whose most famous proponent is the Greek physician Hippocrates of Cos [c. 460–377 BC]), as well as the concept of vital energy (qi) coursing through meridian channels in traditional Chinese medicine.

Alexandria – First Human Dissections

Considering the above, it is surprising that the first human dissections in the history of science took place within the ancient Greek colony of Alexandria in Egypt. The Greek physician Herophilus (c. 335–280 BC) and his disciple Erasistratus (c. 310–250 BC) are widely credited for doing so and regarded as among the first to conduct anatomical dissections in public, including controversial vivisectory practices on condemned criminals. Over a period of 30–40 years, Herophilus made important anatomical discoveries of the eye, cardiovascular, digestive, reproductive, and nervous systems, some of the structures of which still bear his name today (for example, the posterior confluence of cranial venous sinuses also known as the torcular Herophili) [8]. On the other hand, Erasistratus sought to correlate disease states with changes in certain organs – one example being the association of ascites with a hardened liver [9].

Why then, was it possible for Herophilus and Erasistratus to defy traditions and dissect human cadavers? Some reasons have been proposed by von Staden [6] in his work on exploring the cultural contexts of human dissection in ancient Greece. First, democracy was absent in Alexandria which was ruled by Ptolemaic monarchies; not only did the Ptolemies control political action and religious life, but they also wished to establish Alexandria as a centre of scientific learning and had handed over criminals for the purpose of vivisectory experimentation. Moreover, Stoicism and Epicureanism were on the rise during this period; according to the Stoics and Epicureans, death was merely a change in the state of matter and human corpses should not be feared.

Equally surprising as the way systematic anatomical dissection was pioneered was its complete abandonment after the days of Herophilus and Erasistratus, and nobody had attempted another human dissection for centuries until it was eventually restarted in the Middle Ages. Traditional Greek beliefs about the human corpse prevailed once more, and a new “Empirical” doctrine was gaining traction. The Empiricists’ method of practising medicine was based solely on experience (empeiria) and favoured clinical results over identification of “hidden causes,” as the latter was deemed unnecessary and impossible in principle [6]. Moreover, Herophilus and Erasistratus did not establish a new doctrine in place of the well-accepted Hippocratic theory, and with the majority of their manuscripts at the Alexandrian library burnt in 48 BC due to a civil war, their work ultimately received limited recognition.

Galen of Pergamon

A search for “hidden causes” of disease was resumed during the second century by Galen of Pergamon (c. 129–216 AD), a prominent Greco-Roman physician and philosopher who pursued anatomical knowledge through principles of experimentation and reasoning. He considered anatomy essential to understanding physiology, which in turn offered access to the comprehension of pathology [10]. Because dissection of human cadavers was still forbidden in Rome where Galen practised, much of his anatomical work involved animals such as pigs and the Barbary macaque ape. Notwithstanding the shortcomings of extrapolating animal findings to man, Galen was the first to show that urine was formed by the kidneys instead of the bladder and that arteries contained blood instead of the vague life-providing substance that others termed “pneuma” [11]. Galen’s voluminous writings surpassed that of any other author in antiquity, totalling more than 600 treatises [10] and had a long-lasting influence on medical science for the next 1,300 years [11] including the Middle Ages and Renaissance.

What is unusual, nevertheless, was Galen’s fervent belief in the four humours (blood, yellow bile, black bile, and phlegm) despite his considerable understanding of human anatomy and physiology. This conundrum is perhaps reconciled by his general definition of disease as having to fulfil the conditions of (1) a physical condition or constitution that is (2) contrary to nature and (3) impedes biological activity or function [12] – a definition which can be realized with different (and even conflicting) models of disease causation. For all the merits of this definition, Galen’s doctrine did not seem to unify the dynamic pathology of humoral theory with the anatomy-based approach to pathology that he extensively wrote on.

Middle Ages and Renaissance

The Middle Ages, also known as the medieval period, encompassed the next chapter of European history which extended from the fall of the Roman Empire in the fifth century to the beginning of the Renaissance in the 14th century. Prominent medical writers of the time were from the Byzantine and Arabic empires who adopted Galen’s teachings but overall did not make significant advances in the study of disease. Conversely, most changes that did occur during this period were characterized by changing attitudes toward the practice of human dissection, as Roguin et al. [13] succinctly concluded in their review. Selected events of the Middle Ages are presented in Table 1 to illustrate this.

Table 1.

Significant events of the Middle Ages reflecting changing attitudes toward human dissection

Public dissections when they became commonplace were typically performed by a barber-surgeon instead of the anatomy lecturer, who would be seated in an elevated chair reading from an anatomy text while an ostensor pointed out various findings with a rod (Fig. 1). The act of dissecting a human corpse was deemed repulsive and dirty, and research at the dissecting table was regarded as an endeavour of low value. Moreover, studying established texts was deemed the sole way to obtain anatomical knowledge [18]. Consequently, Galen’s writings such as De usu partium (“On the Usefulness of the Parts of the Body”) and De Anatomicis Administrationibus (“On Anatomical Procedures”) remained the indisputable anatomic authority of the Middle Ages with little impetus for change.

Fig. 1.

Lecture in dissection during the Middle Ages, as depicted in Johannes de Ketham’s Fasciculo de Medicina of 1491. Image in public domain and available at http://resource.nlm.nih.gov/101435459 (courtesy of The National Library of Medicine, Bethesda, USA).

This would eventually be challenged during mid-Renaissance by the Belgian physician Andreas Vesalius (1514–1564), who is widely regarded as the father of modern anatomy. As a medical student, Vesalius would notice discrepancies between Galenic text used in anatomy lectures and his own observations – such as concerning the structure of the human mandible – which Galen described as being composed of two parts, while he only identified one [19]. Wanting the “liberty to compare the dicta of Galen… with the tangible facts of bodily structure” [20], Vesalius carried out dissections personally and made more than 200 corrections to anatomical mistakes in Galen’s works [21]. Together with artist collaborator Jan van Calcar (1499–1546), Vesalius published his magnum opus De Humani Corporis Fabrica (“On the Fabric of the Human Body”) in 1543, a seven-volume collection of anatomic illustrations [22] which revolutionized how anatomical investigations were conducted. In the same year, Nicolaus Copernicus’ seminal work on heliocentric theory would herald the era of New Science in which outdated schools of thought were rejected in favour of the search for truth.

Organ and Tissue-Based Pathology

In addition to academic anatomical dissections, autopsies were also performed abundantly throughout the sixteenth to eighteenth centuries. These were recorded in compilations such as the Sepulchretum by Theophile Bonet (1620–1689) which featured over 3,000 autopsies, as well as the monographs of Herman Boerhaave (1668–1738) which emphasized the importance of clinical history when conducting autopsies [16]. At this point, two observations can be made. First, the movement to dissect human cadavers (either for anatomical science or for the autopsy) was in full swing, free of religious and cultural prohibitions which were present for most of classical antiquity. The second observation is that despite increasing numbers of dissections performed, information yielded was largely descriptive. Without purposefully correlating clinical symptoms with anatomical lesions found at the autopsy, little insight was gained in terms of pathogenesis.

The first person to show that diseases arose from organs was the Italian anatomist and physician Giovanni Battista Morgagni (1682–1771). Describing the human body as a machine composed of several devices (organs), Morgagni theorized that a break of a given device (anatomical lesion) would lead to a mechanical problem (disease) [23]. To substantiate this mechanistic philosophy, Morgagni would perform autopsies on patients previously treated by himself – a brilliant enterprise which allowed him to correlate clinical symptoms (ante-mortem) with post-mortem findings. In his monumental work De Sedibus et Causis Morborum per Anatomen Indagatis Libri Quinque (“The Seats and Causes of Diseases Investigated by Anatomy”) published in 1761, Morgagni detailed his pathologic observations collated over a lifetime from about 700 autopsy dissections [24] and emphasized the importance of the anatomoclinical method. Till today, Morgagni’s approach to anatomoclinical correlation is found under the guise of clinicopathological conferences, which were inaugurated at Harvard Medical School at the beginning of the twentieth century [25].

Marie-Francois Xavier Bichat (1771–1802), a French surgeon and anatomist, subsequently added to the work of Morgagni by introducing the concept of “tissues.” He likened anatomy to chemistry, positing that a combination of simple tissues formed organs, in the same way as “simple bodies” such as hydrogen, oxygen, and carbon formed compound structures through various combinations [26]. Through methods such as boiling, soaking, baking, and tissue reactions to acids or bases [27], Bichat identified 21 types of elementary tissues, some of which included nerves, blood vessels, muscles, fibrocartilaginous tissue, and serous membranes [28]. On the basis that “one [tissue] may be impaired without disorder of the others” [26], he accurately refined diagnoses by specifying the tissue that was diseased, for example, through the subdivision of carditis into pericarditis, myocarditis, and endocarditis [29].

Microscopy and Cellular Pathology

The next major development in pathology was – as the reader might have guessed by now – cell theory and cellular pathology, which in turn relied on the invention of microscopy. The identity of the microscope’s inventor is contentious, and the earliest microscopes suffered from various optical problems, but we know that by 1665, the English scientist Robert Hooke (1635–1702) coined the term “cell” while studying oak tree bark [30]. Around the same time, Antoni van Leeuwenhoek (1632–1723) provided the first description of sperm cells, red blood cells, and bacteria (which he called “animacules” or “little eels”). This was made possible with Leeuwenhoek’s handheld, single-lens microscope of 250 times magnification (Fig. 2), which was likely developed to inspect the quality of cloth that he sold as a draper [31]. Despite the potential of microscopy in medical research, Leeuwenhoek’s discoveries were briefly forgotten, and the microscope was not widely used until the nineteenth century – for which conceivable reasons included high costs, technical difficulties, misuse as a toy, and a lack of ideas regarding objects which were to be examined [32].

Fig. 2.

Replica of Leeuwenhoek’s single-lens microscope, which comprised a pointed tip on which the specimen was placed. A series of screws allowed the user to change the image focus and to move the object along different axes. Image courtesy of Jeroen Rouwkema, available at https://commons.wikimedia.org/wiki/File:Leeuwenhoek_Microscope.png.

When microscopes with improved optics became available in the nineteenth century, Johannes Müller (1801–1858), professor of anatomy, physiology, and pathology at the University of Berlin was one of the first to employ the tool in studying cancer. His book Ueber den feineren Bau der krankhaften Geschwülste (“On the nature and structural characteristics of cancer”) is commonly considered the first histopathology book, showing cancer to be a growth of abnormal cells in contrast to the then prevailing belief that cancer was a general disease (of which the tumour was a local manifestation) [33]. Müller insisted upon the use of microscopy in studying pathology [34], and from his laboratory emerged Mathias Schleiden (1804–1881) and Theodore Schwann (1810–1882) who founded the cell theory; Schleiden proposed that all plant structures were composed of cells or their products, while Schwann generalized this to all living organisms.

Inspired by Schwann’s work, Rudolf Virchow (1821–1902) considered the cell as basic to the understanding of disease and wrote in Die Cellularpathologie in 1858: “Each disease originates from the alterations that affect a smaller or larger number of cellular units within the living organism; every pathological disturbance, every therapeutic effect can only then have interpreted, when it is possible to tell which particular group of living cellular elements is concerned, and which kind of alterations each element of such a group has undergone. The long searched for essence of disease is the altered cell [35].” With cellular pathology defined as such, Virchow showed the relationship between gross pathological changes and their corresponding cellular alterations [36], sweeping away any lingering misconceptions regarding humoral theory and the role of bodily fluids in their causation of disease.

At the same time, a discussion of the microscope’s role in pathology would be incomplete without mention of histopathology techniques. Michael Titford’s review [37] offers a delightful insight into how this field developed, and key milestones are outlined in Table 2.

Table 2.

Discovery of selected histopathology techniques

Dawn of Microbiology

The microscope offered an additional dimension to pathology with the emergence of microbiology in the latter half of the nineteenth century. A case is made by Rosati [42] that “If … the microscope invented the pathologist, it was the microbe, especially the pathogenic bacterium, that gave him his name and made him clinically relevant.”

Foundations of germ theory were laid between 1857 and the 1860s by French chemist Louis Pasteur (1822–1895), who identified that microbes caused fermentation as opposed to chemical decomposition. In a series of experiments using the famous swan-neck flasks (Fig. 3), Pasteur also showed that microbial growth in nutrient broths was due to environmental contamination rather than spontaneous generation [43]. In 1876, German physician Robert Koch (1843–1910) would conclusively demonstrate the infectious nature of anthrax. In his paper titled “The Etiology of Anthrax, Based on the Life History of Bacillus anthracis,” Koch clarified the natural life cycle of Bacillus anthracis and effectively infected animals with the organism [44]. Koch’s next major work in 1880 suggested that tuberculosis was also an infectious disease, a finding which was met with opposition by Rudolf Virchow, who viewed the disease to be a consequence of malfunctioning host cells without external causes. In response, Koch formulated a set of criteria which sought to prove a causal relationship between microorganisms and disease, known today as the Koch’s postulates [44].

Fig. 3.

The swan neck of Pasteur’s flasks trapped microbial organisms from air and prevented their contamination of a nutrient-rich broth within the flask. No bacteria appeared in pasteurized broth initially, but after the flask was tipped over to allow contact of the broth with the neck, bacteria started to multiply within. Image courtesy of Wellcome Images, London, UK, and available at https://commons.wikimedia.org/wiki/File:Swan-necked_flask_used_by_Pasteur._Wellcome_M0012521.jpg.

These discoveries had an enormous impact on pathology as they explained the fundamental causes of infectious disease, which was responsible for most of the morbidity and mortality of the time until the twentieth century. Knowledge of microbiology also reshaped clinical practice, and this was made apparent by the British surgeon Joseph Lister (1827–1912) who introduced in 1867 the use of diluted carbolic acid for treating compound fractures and sterilizing skin prior to surgical incisions, measures which led to better patient outcomes [45]. By the last decades of the nineteenth century, many pathologists had been attracted to the new fields of microbiology and experimental pathology, and medical schools with departments headed by “Chairmen of Pathology and Bacteriology” became increasingly established [42].

Immunohistochemistry and Molecular Techniques

At the turn of the twentieth century, pathologists were significantly engaged with the study of neoplastic diseases, paying particular attention to tumour morphology, classification, and histogenesis [46]. Examination of formalin-fixed, paraffin-embedded tissue stained with haematoxylin and eosin was considered “Gold Standard” at the time of 1900 for establishing diagnoses, although accuracy would have been limited by subjectivity in identifying morphologic features. An objective method to specify cell types was needed, and early approaches at differentiating cells based on enzymatic activity were futile due to the inactivating effects of formalin fixation [47].

In 1941, Albert Coons (1912–1978) and colleagues from Harvard University successfully visualized pneumococcal antigens in infected tissue specimens using fluorescently labelled antibodies [48]. Describing the thoughts behind this remarkable achievement, Coons famously wrote: “It struck me that this theory [of a hypersensitivity reaction causing formation of the Aschoff nodule in rheumatic fever] had never been tested and indeed could not be tested without the demonstration of antibody or antigen, preferably both, in the local lesions. I considered that it might be easier to find the antigen than the antibody, for a start anyway, and that what was required was a visible microprecipitate. The notion of labelling an antibody molecule with a visible label was perfectly obvious in such a context [49].”

Subsequently, in 1975, Georges Köhler (1946–1995) and César Milstein (1927–2002) developed the hybridoma method of producing monoclonal antibodies [50], giving the technique of immunohistochemistry a huge boost by increasing the repertoire of antibodies available. With the conception of the structural model of DNA [51] by James Watson (1928) and Francis Crick (1916–2004), the invention of Sanger sequencing [52] by Frederick Sanger (1918–2013), and the discovery of polymerase chain reaction [53] by Kary Mullis (1944–2019), it became possible to delve further into the cell for genetic causes of disease, redefining how various malignancies are classified today.

Conclusion

Mankind has long been fascinated by disease, keeping records of its manifestations as early as 1700 BC. Identification of disease causation was essential to the development of cures, and therefore, the history of pathology is closely intertwined with the history of medicine itself. A single watershed moment which defines the birth of pathology does not exist, and notwithstanding the inevitable risks of brevity and oversimplification, this article aims to outline significant milestones which have shaped the practice of this medical science, with more historical than modern day emphasis. These include (1) the changing public attitudes toward human dissections over time, which paved the way for anatomical pathology and localization of disease to organs and tissues; (2) the rise of cellular pathology and microbiology with the invention of the microscope; and (3) the increasingly sophisticated technologies of the 20th and 21st centuries which facilitated the practice of molecular pathology. At this point, one may ponder: what does the future of pathology hold? The use of artificial intelligence as an assistive tool in diagnosing malignancy has been described recently [54] and may prove to be an interesting development to watch out for.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors did not receive financial support for the original research. Publication costs of this article were funded by the SingHealth Duke-NUS Pathology Academic Clinical Programme after the research was conducted and submitted for publication.

Author Contributions

Dr. Edwin Jun Chen Chew conducted research on the subject matter and drafted the manuscript; Dr. Puay Hoon Tan conceived the study and oversaw the writing of this paper. All authors read and approved the final version.

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