The emergence of Pathology

Introduction
From Anatomy to Pathology
Infectious Pathology
Genetic Pathology
Nutritional Pathology
Immune Pathology
Topics for Exam
Further Readings
Further Links

Introduction

This course focuses primarily on the Biology of Disease. It discusses nevertheless related concepts and facts, whether anthropological or social, that are known to impact on disease
development in order to offer students a comprehensive understanding of disease. This =irst lecture does not discuss or de=ine disease but merely the approaches through which diseases have been
studied in the western world . Lectures 2 and 3 will cover, among other topics, the de=inition and general causes of diseases.

Every culture that mankind has developed has tackled concepts such as life, death and disease and a comparative analysis of the approaches that different cultures have offered is highly
informative. Western culture has followed a distinct path in this endeavour because whereas the majority of other cultures have regarded disease as an imbalance between the body and the
surrounding world, in much of western culture disease has been seen as an imbalance within the body and studied primarily as such.

Pathology is the discipline that speci=ically addresses the disease process, its mechanism and its impact on the structure and function of the body, its organs, tissues and cells. The discussion
below covers the major stpes in the development of Pathology as a modern discipline.

From Anatomy to Pathology

Modern Pathology developed from Anatomy in Renaissance Italy. At the same time at which artists such as Michelangelo and Leonardo conduct autopsies in order to paint or sculpt the human
body with knowledge of its parts and working, Antonio Benivieni, a Florentine medic, undertakes autopsies in order to understand the causes of death and the patient's symptoms (see Fig A
Benivieni's early insights into Pathology). Benivieni's accounts are published posthumously in 1507 and can certainly be regarded as the =irst stone in the edi=ice of modern Pathology. It is also in
Renaissance time (in 1543) that the Frenchman Jean Fernel introduces the terms Physiology and Pathology in the medical vocabulary.

Benivieni's work was preliminary in nature (he carried out and reported a total of 20 autopsies) and completion of the research programme that Benivieni had initiated had to wait for another
two and half centuries and speci=ically for GB Morgagni (1682-1771). GB Morgagni's opus proved monumental. Throughout his life he had executed over 700 autopsies and the work that he =inally
released for publication 2 years before his death culminates Benivieni's early ambition to correlate and understand the anatomical basis of symptoms and disease process.

Morgagni's superb description of the gross anatomical basis of disease underwent two futher developments, an important one and a dramatic one. The important change occurred in Paris
through the work of Xavier Bichat. Morgagni had described the changes induced by disease at a macroscopic level. Xavier Bichat was not content of cutting sections across each organ for inspection
by naked eye, as Morgagni had done. Instead he did tear apart a variety of organs by chemical, mechanical or other physical methods and established in his Traite' de Membranes, which he
published in 1799 that organs are composed of tissues. He also noted that similar tissues are present in different organs and react in a similar manner during the disease process. Bichat therefore
introduced General Pathology, as the study of these common disease processes that reoccur in different tissues across the body.

1 of 5
 The gigantic leap forward followed the proposal and acceptance of the cell theory of Matthias Jacob Schleiden and Theodor Schwann. Although the word cell had been introduced much
earlier (by Robert Hooke in 1664), Hooke's cell denoted a box, a space. In contrast the German botanist and animal physiologist realise that cells constitute the complex and fundamental building
block of living organisms. Building on this work another German, namely Rudolph Virchow put forward the concept that the diseases of the body have their basis in structural (ie morphological)
alterations of the cells. Furthermore, following upon skilfull experiments carried out by Robert Ramek (a Jewish Pole working in Berlin at the margin of the academic community, due to the anti-
Jewish feelings that had started to develop in German society), Virchow espoused Ramek's conclusion that each cell originates from an existing cell via cell division (omnis cellula a cellula).

The manifesto of Virchow's new Pathologie, exposed in his Die Cellular Pathologie published in 1858 was - and remains today - that the causes and the mechanisms of disease have to be
studied and understood at the level of the cell and through the changes that they impose on their structure, ie their morphology and working. Virchow's impact on Medicine, though, was not con=ined
to his outstanding contributions from the laboratory. A believer in social progress and greater equality, when he returned to Berlin in 1856 from Würzburg to direct the Pathological Institute, he
founded the Progressive Party, was elected into Parliament and promoted radical programmes of social hygiene and education. He was also alarmed by the growing support for the concept of a
superior German race and fought against this ideology and the accompanying anti-Semitism from the strength of scienti=ic reasoning.

Infectious Pathology

The anatomical foundation outlined above is the =irst and main corner stone of Western Pathology but it is not the only one. Contemporary Pathology also builds on a strong foundation of
Immunology and Bacteriology that emerged in the attempt to bring infectious diseases under control. This work has been covered in more detail in the Immunology lectures but will be outlined here
in order to ensure that students develop a comprehensive and integrated view of the subject.

The =irst attempts to formulate a theory of contagion, namely the transmission of certain diseases among close family or community members, goes back to Renaissance time. In the 14th
century Europe had been devastated by the Black Death (bubonic plague), which killed 20 million people between 1347 and 1351, over a quarter of the whole population and the =igures were even
worst in large cities (Florence, for example lost over 60,000 of its 100,000 people). Smallpox had also emerged strongly in Europe and for centuries exacted a huge toll from European populations.
The =irst attempt to offer a general theory of contagion, however, stemmed from the interests in syphilis by Girolamo Fracastoro, an Italian physician and humanist. Syphilis was another contagious
disease that had become common in Europe in the early part of the 16th century (whether it was imported from the Americas, it has not been proved conclusively). Fracastoro's work published in
1546 (De contagione et contagiosis morbis curatione or On contagion and the cure of contagious diseases) proposed that the agents of contagion were small particles (seminaria) transmitted
through the air. This was a departure from the common notion that polluted air was to blame although Fracastoro's falls short of attributing living properties to his seminaria.

The germ theory of disease as we now know is rooted in the work of L Pasteur, R Koch and their coworkers in the latest part of the 19th century but interest in such a theory had built up in
earlier decades. In 1835 Agostino Bassi, a farmer facing the destructive effects of muscardine, a silkworm disease, noted the presence of a fungus on dead silkworms and succeeded in transferring
the disease by transferring the fungus from infected to non infected silkworms. In 1940 Jacob Henle in his Pathologische Untersuchungen or Pathological Investigations attributed contagion to
'micro-organisms with a life of their own and a parasitic relation with the sick body'. The theoretical foundations of the germ theory of disease had been clearly laid out and experimental
evidence in support of Henle's theory was on its way from L Pasteur and R Koch.

In 1860 Louis Pasteur established the living (rather than the merely chemical) nature of fermentation, settled once and for the ever the issue of putrefaction and spontaneous generation
(with clever experimental design, ie =lasks with a bent neck and a cotton plug to prevent entry of micro-organisms in the organic matter and hence 'spontaneous generation' and devised techniques
(heating at 55 C for suitable times) that protected wine from soaring and milk from transmitting cattle tuberculosis to man. Further, in 1978 in front of the French Academy of Sciences, he openly
proclaimed that contagion was due to living agents similar to the ones responsible for fermentation and putrefaction. As discussed in the Immunology lectures he followed words with facts: he

2 of 5
 discovered the agent responsible for chicken cholera as well attenuation enabling him to develop vaccines against the agents causing chicken cholera, anthrax and rabies.

Work in Berlin, in the same years set the foundations of bacteriology as a science through the development of rigorous protocols for the isolation and culture of bacteria and rigorous criteria
for establishing a micro-organisms as the true cause of disease (Koch's postulates). In the last two decades of the 19th century the new science of bacteriology under Koch will yield the bacteria
responsible for cholera, tuberculosis, diphteria, tetanus and several others. Further, it will immediately offer a way for changing the course of diphteria and tetanus through serotherapy.

Within another few years smaller, =ilterable agents causing plant diseases were discovered by D Ivanovsky (1892) an M Beijerinck (1898) and named viruses . This was followed by the
discovery of similar agents causing animal and human disease and led to the emergence of the modern science of Virology. Hence at the start of 20th century Pathology the whole edi=ice of western
Medicine found itself transformed by the theoretical and practical advances that Bacteriolog, Immunology and Virology.

Genetic Pathology

G Mendel had uncovered the basic rules of transmission of heritable traits through clever hybridisation experiments on garden peas but the impact of genetics on Pathology and Medicine
emerged much later. Instrumental in this were careful clinical observations of inherited diseases such as alkaptonuria, 'an inborn defect of metabolism' uncovered by A Garrod at the end of the
19th century in London.

Another example destined to acquire a gigantic role in modern Medicine was the initial description of sickle-cell anemia (images/sickle_cell_anemia1.jpg) , a severe anemia characterised by the
distinctive presence of red blood cells shaped like sickles described by JB Herrick in Chicago in 1910 and the subsequent demonstration of the inherited nature of this disorder by JB Hick.

L Pauling and his colleagues isolated hemoglobin from a patient with sickle-cell anemia and reported in 1949 in an article on Science that the physico-chemical properties, ie the
electrophoretic beahviour, of sickle-cell hemoglobin differed from the normal one (see image Molecular medicine. I).

3 of 5
 These results led Linus Pauling to propose that the difference between the variant hemoglobin must have resided in the amino acid composition and/or sequence rather than the heme, a
prediction that was con=irmed in 1956 and 1957 by Vernon Ingram working at the MRC Laboratory in Cambridge through rigorous demonstration that sickle-cell hemoglobin differed from the
normal one by a single amino acid replacement at position 6 of the beta chain where a Glu in the wild type allele is substituted by a Val in sickle-cell anemia (see image Molecular medicine. II).

The complex population genetics underlying the presence and the propagation of the sickle-cell (S) hemoglobin will be discussed in a separate lecture but here I would like to add here that
physico-chemical and structural studies have clari=ied that the hemoglobin S has reduced solubility compared to hemoglobin A and forms rigid array that ultimately cause the sickle-cell phenotype.

Nutritional Pathology

There is incontrovertible evidence for the link between inadequate food supply and disease. In many instances this has been caused or at the very least aggravated by the deliberate action of
man and there is an exceedingly long list of such events in human history. I will illustrate the point here with the Irish famine of 1845-7 when, in the short period of a 2-3 years more than a million
people died (out of a total population of 8 million) and another 2 millions emigrated . The Irish famine was caused by consecutive losses of the potato harvest due to potato blight, a disease of the
potato plant caused by the fungus Phytophthora infestans. Importantly for the sake of this lecture, the majority of the deaths were caused by infectious diseases, such as typhus, relapsing fever,
dysentery. Hence, the loss of immunity caused by starvation caused death in the last instance.

Approximately half a century later, experimental studies as well as clinical observations on groups of people on poor diets established that diseases such as scurvy, rickets, pellagra and
beriberi were caused by the lack of dietary component(s). These components were named vitamines by the Polish biochemist Casimir Funk, who was actively engaged in research on these
molecules.

In the case of nutritional pathology and diseases, therefore, it is the lack of a necessary components that triggers cell and tissue damage, unlike the other mechanisms discussed here
(infectious, immune, etc) in which it is the presence of speci=ic micro-organisms (or their products) or the presence of speci=ic antibodies or T cell clones that triggers potentially a disease status.

Immune Pathology

In the Immunology lectures the key experiments and observation that led to the concept that the immune response could damage the cells and tissues of the host and thus harm the host were
presented and students areinvited to revise this material as a way of understading the meechanisms by which immunity can, in certain circumstances, cause disease.

Topics for Exam

From Anatomy to Pathology

Foundations of Cellular Pathology
Germ Theory of Disease
Origin of Molecular Medicine

Further Readings

[1] Porter R. The greatest bene=it to mankind. A medical history of humanity from antiquity to the present. Fontana Press, 1999.

[2] Virchow R. Cellular pathology as based upon physiological and pathological histology (readings/virchow_1860.pdf) . Translated from the 2nd edition of the original by F Chance. 7th
American edition. RM De Witt, New York (1860).

[3] Florey HW. The history and scope of pathology. In General Pathology. Lord Florey (ed), 4th ed. Lloyd-Luke (Medical Books) Ltd (1970)

4 of 5
 [3] Sickle Cell Anemia, a Molecular Disease (readings/pauling_1949.pdf) . Pauling L et al Science 109:443 and 110:543-8 (1949).

[4] A speci[ic chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin (readings/ingram_1956.pdf) . Ingram VM Nature 178: 792 (1956)

[ 5] Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell anaemia. (readings/ingram_1957.pdf) Ingram VM Nature 180:326 (1957)

[6] The high resolution crystal structure of deoxyhemoglobin S (readings/harrington_1997.pdf) . Harrington DJ et al J mol Biol 272: 398: 1997

Further Links

5 of 5