Rudolf Virchow's Medical School Dissertation on Rheumatism And

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Rudolf Virchow’s Medical School Dissertation on Rheumatism and the Cornea: Overlooked Tribute to the Cornea in Biomedical Research

Curtis E. Margo, MD, MPH,*† and Lynn E. Harman, MD*

theory to scientific-based concepts dealing with the cell.1,2 Purpose: ’ To critique Rudolf Virchow s medical school dissertation The event that usually marks this transition was a series on rheumatism and the cornea and to determine whether it might of biweekly lectures delivered at the Pathological Institute have anticipated his remarkable career in medicine. of the University of Berlin. From February through 3 Methods: Review of the English translation of Rudolf Virchow’s April 1858, Virchow introduced his doctrine of cellular de Rheumate Praesertim Corneae written in 1843. pathology, casting aside generations of conjecture about the nature of illness with the observation that the true Results: The dissertation was more than 7000 words long. Virchow nexus of disease resides in the chemical and physical considered rheumatism as an irritant disorder not induced by acid as activities of cells. Virchow used transcripts of these traditionally thought but by albumin. He concluded that inflamma- lectures to write his landmark text Cellular Pathology, tion was secondary to a primary irritant and that the “seat” of published later that year. The thesis of Cellular Pathology rheumatism was “gelatinous” (connective) tissues, which included was expressed so clearly and forcefully that popular the cornea. He divided kerato-rheumatism into different varieties. theories such as vitalism and humoral pathology were The prognosis of keratitis was variable, and would eventually lapse doomed to irrelevance. into “scrofulosis, syphilis, or arthritis of the cornea.” Although he was just 37 years old when he wrote Cellular Pathology, Virchow had become the leading voice Conclusions: ’ Virchow s dissertation characterizes rheumatism in in European medicine (Fig. 1). His ascent to chair the terms of chemical and tissue interactions that make little sense in the prestigious Pathology Institute and to become the editor ’ context of today s knowledge of rheumatic disease and keratitis. editor of Archives of Pathological Anatomy, Physiology, Ironically, many of these concepts were made obsolete by the cellular and Clinical Medicine was due to his skills as a microscopic model of disease that Virchow championed. Virchow decided to pathologist and his ability to synthesize biomedical obser- pursue the study of rheumatism through the cornea because he thought vations into theories and testable hypotheses. Fifteen years that the cornea was an ideal tissue to study disease. This discernment earlier, Virchow had written (in Latin) his medical school was passed on to his students whose seminal contributions to general dissertation on rheumatism and the cornea. With no more pathology were based on research with the cornea. It is debatable background than a single ward experience at the Charité ’ whether Virchow s insight into the importance of the cornea in Hospital, he completed his dissertation on October 21, biomedical research at such an early stage of his career could have 1843, the day he graduated from Friedrich Wilhelm predicted his monumental contributions to medicine. University. Cost of privately printing the document was Key Words: rheumatic keratitis, Ruldolf Virchow, ophthalmic paid by his father, who gave the work to his friends. We history reviewed Virchow’sdissertationde Rheumate Praesertim Corneae to determine whether this inaugural work could (Cornea 2015;34:235–238) have anticipated the prodigious accomplishments that were to lie in his future. udolf Virchow (1821–1902) was arguably the single Rmost influential physician in modern medicine, having MATERIALS AND METHODS steered the profession away from centuries of metaphysical Rudolf Virchow’s dissertation de Rheumate Praesertim Corneae was translated from Latin by Leland J. Rather and is found in an appendix to a volume of letters Virchow wrote to Received for publication October 14, 2014; revision received October 29, his parents from 1839 through 1864.4 Literally translated “On 2014; accepted October 30, 2014. Published online ahead of print ” December 18, 2014. Rheumatism, Especially of the Cornea, the dissertation will From the Departments of *Ophthalmology, and †Pathology and Cell Biology, be referred to as rheumatism and the cornea. The text is Morsani College of Medicine, University of South Florida, Tampa, FL. approximately 7200 words and has no illustrations. After the The authors have no funding or conflicts of interest to disclose. preface, it is organized into 28 sections, many of which are Reprints: Curtis E. Margo, MD, MPH, Department of Ophthalmology, Morsani College of Medicine, University of South Florida, MDC 21, 12901 Bruce just a single paragraph. The translation is accompanied by B. Downs Blvd, Tampa, FL 33612 (e-mail: [email protected]). a 3-page forward by L. J. Rather, Emeritus Professor of Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Pathology at Stanford University.

Cornea Volume 34, Number 2, February 2015 www.corneajrnl.com | 235 Margo and Harman Cornea Volume 34, Number 2, February 2015

currently accepted theory of pathogenesis, explicitly that a “morbid substance mixed in the blood is carried to various organs and excites in them an irritation that resembles inflammation.”4(p161) Traditional teaching had implicated acid as the irritating substance, but Virchow cited more recent research in medical chemistry by Justin Liebig (1803–1873) that incriminated albumin as the putative substance. He dismissed the importance of other causes of rheumatism such as aberrant electricity by not discussing them. Nearly half way through the dissertation, Virchow reviewed the anatomy of the cornea. Citing the work of others, he described the stroma as consisting of bundles of extremely delicate fibrils “that run everywhere in conjoined networks, leaving hollow areas of free spaces.”4(p167) The horizontal fibrils were covered by an epithelium. The fibrils are transparent and gathered together by lattices running in vertical and oblique directions. He described a “humor” within the cornea but stated that its origin was controversial. Nothing in the anatomic description of the cornea appeared to correspond to Descemet membrane or the endothelium. Virchow stated that the healthy cornea did not contain blood vessels, and later concluded that vascularization was patho- gnomonic of inflammation. The middle part of the dissertation was devoted to a discussion on rheumatism and the cornea. Virchow divides corneal involvement into 3 varieties: (1) simple, (2) kerato- rheumatism, and (3) torpid. In the simple variety, fever is rare and the cornea becomes cloudy, or whitish or bluish. He credits Jüngken with observing that the surface of the cornea is eroded, depressed, or elevated (the latter suggested to Virchow the possibility of phlyctenule). As the disease progressed, nerves are affected resulting in photophobia, miosis, pain, and tearing. In kerato-rheumatism, the substance that triggers the disorder enters the cornea and then provokes inflammation. Corneal vascularization characterizes the early stages of this variety, which explained why other clinicians have referred to it as rheumatic vascular keratitis. Virchow cited Jüngken who described the “corona of vessels” that surrounds the margin of the cornea as characteristic. As inflammation intensifies, these vessels can become confluent appearing as a “bloody fillet.” In the final stages of the disorder, the entire cornea is ’ FIGURE 1. obscured by vessels visible to the naked eye. To Virchow s Limestone monument honoring Rudolf Virchow in knowledge, no early stage of kerato-rheumatism had been Karlplatz, Berlin. The sculpture that caps the monument has provoked a variety of interpretations (personal collection of studied pathologically. the author). The third variety of corneal rheumatism was torpid, but which Jüngken called scrofulous keratitis. Virchow believed that this type of keratitis represented a chronic form of either RESULTS of the 2 previous varieties, but did not elaborate further on Virchow began his dissertation by providing background pathogenesis. on how he became interested in the subject of rheumatism and The remaining portion of the text described the chronic the eye through his medical school mentor Johann Christian nature of rheumatic keratitis, regardless of variety. Incomplete Jüngken (1794–1875). A surgeon at Charité Hospital, Jüngken, healing and abscess formation were 2 undesirable outcomes. cared for a number of persons having eye disease. Virchow Virchow drew on the similarities of rheumatic phlyctenae of the justified his study by explaining that “the rubric of ophthalmia” cornea and miliary rheumatism, arguing that phlyctenae of the for which ocular inflammations were collectively referred, was cornea are a form of rheumatic exanthema. It is unclear whether too broad a category for meaningful. He hoped to shed light on Virchow added any newly created information to the literature rheumatism of the cornea by separating it from other or simply reviewed and discussed what was already known. ophthalmias for specific analysis. After acknowledging that Virchow ended his dissertation abruptly with 2 rheumatism affects others parts of the body, he described the thoughts: First that “incomplete healing with metastases of

236 | www.corneajrnl.com Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved. Cornea Volume 34, Number 2, February 2015 Tribute to the Cornea in Biomedical Research kerato-rheumatism occurs,” and second that “Last of all, our was occasionally awakened at odd hours of nights to bleed disease passes over into scrofulosis, syphilis, or arthritis of patients for Jüngken.7(p139) Although Virchow professed the cornea.” familiarity with corneal microscopy, it is doubtful he studied any new cases of keratitis for his dissertation. If he had, histological sections of corneas had to be cut with a hand-held DISCUSSION razor blade. Few histological dyes were available, therefore it is Classification of diseases in mid 19th century was arcane likely that he examined sections unstained. Good quality largely because no scientific concept of causality existed. But microscopes were also uncommon. Compound microscopes medical jargon was also stultifying, which makes interpretation after 1829 usually used lenses corrected for chromatic of historical documents such as Virchow’s dissertation tenta- aberration, but resolution was often limited by spherical tive. The subject of his dissertation was “rheumatism” of the aberration in all but the most expensive.8 Based on available cornea, but what clinical entities this might have included in documents, neither professor Jüngken nor Müller directly terms of modern taxonomy is unclear. Systemic findings other oversaw Virchow’s dissertation.7(p140) Virchow would have than fever and arthritis were not mentioned in sufficient detail been left to master the art of processing, cutting, and to draw any conclusions about the nature of the rheumatic interpreting tissues with limited instruction and supervision. maladies with which he was dealing. Virchow cited the works of 68 others in his dissertation, As a medical student, Virchow likely learned how to familiarity with the medical literature he would become diagnose rheumatism from his instructors. Noted authorities renowned for later in life. such as Thomas Sydenham (1628–1694) or William Cullen When Virchow graduated from medical school, (1712–1790) had defined rheumatism based on symptoms of knowledge about inflammation was primitive. The cellular pain afflicting the joints usually associated with swelling and nature of inflammation would not be elucidated for another erythema.5 Although rheumatic disorders were loosely placed 6 years, when Sir William Bowman (1816–1892) in 1849 into acute and chronic deforming varieties, the reader is left to described the increased numbers of cells that accompany assume that Virchow was interested in corneal changes clinical signs of corneal inflammation. Bowman believed, associated with joint disease in general. One is left to wonder however, that this increased cellularity was due to endog- whether this assumption is correct, however, because Virchow enous cells, so-called fixed corneal corpuscles, which ends his dissertation by relating “arthritis of the cornea” with increased in number when stimulated.9(p615) This under- scrofula (ie, tuberculous adenopathy) and syphilis. It is possible standing was the same as Virchow’s,3 who would elaborate that rheumatism in mid 19th century included significant on it in greater detail under the heading of parenchymatous numbers of infectious arthropathies and not nearly the pro- keratitis in Cellular Pathology. portion of disorders now attributed to autoimmunity. Decipher- Although a neophyte in medicine when he undertook ing what systemic illnesses might have been included under the his student research project, Virchow displayed considerable term rheumatism is not the only challenge to interpretation. perception on how to approach the study of a complex Physicians at this time had little understanding of inflammation. disorder like rheumatism. He thought that the cornea was At the end of his career, Virchow’s bibliography crucial in unraveling the pathogenesis of inflammation, included more than 2000 publications.6 The dissertation on a malady that had stymied physicians for 2000 years. His rheumatic disease of the cornea was his initial academic work. rationale for concentrating on the cornea was offered in his Although its contributions to medicine are obscured by more introductory paragraph: “There is indeed no part of the human than 170 years of progress in biology, it is fair to say that the body more suited than the eye in which to scrutinize the dissertation reveals more about Virchow than it does about nature and course of diseases.”4(p160) This conviction never disorders of the cornea or joints. When he started this project, waned. The insight was fortunately passed on to his students Virchow had completed 3 classroom courses taught by who would use the cornea in research studies that led to Johannes Müller (1801–1858), the foremost anatomist and breakthroughs in the understanding of inflammation. physiologist of his time. Müller was a provocative instructor, Twenty years after Virchow graduated from medical but his legacy has been measured by the men he trained, school, debate over the basic nature of inflammation still which included Theodor Schwann (1810–1882), Jakob Henle festered. Although advances in microscopy had taken place, (1809–1885), Robert Remak (1815–1865), and Hermann von virtually nothing was known about the biological events Helmholtz (1821–1894), to name a few. Müller taught Virchow’s underlying cardinal signs of inflammation. Despite the final course before he started his clinical training at Charité morphological identity of white blood cells in peripheral Hospital. The lectures dealt with pathological anatomy; Virchow blood and “pus” cells, Virchow3 insisted that pus cells took meticulous notes but was given little if any practical originated in connective tissues. By now, Virchow had instruction in microscopy.7(p137) Müller insisted that his students trained a group of talented pathologists, among them think about disease in terms of microscopic anatomy although Friedrich von Recklinghausen (1833–1910) and Julius the science was in its infancy. This guidance must have been Cohnheim (1839–1884), who thought their mentor might inspirational given the contributions his students would make to be wrong about this particular matter. the nascent specialty of pathology. Recklinghausen ran Virchow’s laboratory for several Virchow completed his dissertation while being a student years. He studied pyemia and wandering cells of the on the surgical wards working from 8 AM to 8 PM. The daily connective tissue for nearly a decade before he published routine was demanding, and evenings were unpredictable; he an article in 1855 describing the amoeboid motion of pus

Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved. www.corneajrnl.com | 237 Margo and Harman Cornea Volume 34, Number 2, February 2015 cells.2(p191) He contradicted Virchow by finding no evidence SUMMARY that pus cells arose from a division of existing cells in the Virchow’s medical school dissertation on rheumatism connective tissue. He provided support for the theory that pus and the cornea was an ambitious attempt to understand cells migrate into injured tissues from other locations using a complex disease process by studying its ocular manifes- pieces of cornea implanted into the subcutaneous lymph sacs tations. Although Virchow’s dissertation contributed no of frogs. Some medical historians suggest that because lasting knowledge to the study of rheumatism or keratitis, Recklinghausen feared the repercussions of challenging experience reinforced his belief that the cornea was an ideal Virchow on this subject, he abandoned the research.2(p192) tissue to study disease. This insight was conveyed to his Cohnheim also began his career at the Virchow Institute students who used the cornea in some of the most pivotal working on pus cells. In 1861, he published an historic article experiments in the history of pathology. describing how physical, chemical, and thermal injuries to At the time when Virchow first began his studies on the serosal surfaces induce similar patterns of inflamma- cornea, histological sections were cut with hand-held blades tion.10(p159) In 1864, he replaced Recklinghausen as the chief and often examined unstained. His frustrations in understand- assistant to Virchow and continued his research on origins of ing corneal anatomy during this period must have been pus. Cohnheim induced inflammation in corneas of frogs and, immense. It may seem ironic that Sir Stewart Duke-Elder using a differential staining technique, attempted to distin- credits Hans Virchow (1852–1940), the son of Rudolf, as guish whether leukocytes arose within the cornea or migrated contributing more to our knowledge of microscopic anatomy from outside. The results of his corneal experiments were of the cornea than any single individual.13(p95) It seems that conclusive. There was little doubt that leukocytes in pus were Rudolf Virchow’s passion for his work was so contagious that hematogenously derived through diapedesis.10(p160) Virchow even family members were not immune. would stubbornly defend his position that inflammatory reactions are a consequence of excessive intake of interstitial REFERENCES cells, until Cohnheim published another study showing fl 1. Nuland SB. Doctors. The Biography of Medicine Ch 11. New York, NY: in ammatory corpuscles were the same as blood corpuscles. Vintage; 1988:304–342. Virchow eventually accepted that acute inflammatory cells 2. Malkin HM. Out of the Mist. The Foundation of Modern Pathology and were derived from the blood, but research into inflammation Medicine During the Nineteenth Century. Berkeley, CA: Vesalius Books; proceeded slowly.11 Roughly 40 years after Virchow com- 1993. – 3. Virchow R. Cellular Pathology as Based Upon Physiological and pleted medical school, Ilya Metchniknoff (1845 1916), Pathological Histology. (Translated from the Second Edition by Frank a Russian-born zoologist, provided the quintessential observ- Chance). London, United kingdom: John Churchill; 1860. able response to injury when he demonstrated bacteria being 4. Virchow R. Inaugural Dissertation, de rheumate praesertim corneae ingested by leukocytes.2(p295) (1843), (Translation from Latin by L. J. Rather). In: Virchow R, ed. – On October 13, 1901, Virchow’s 80th birthday, Julius Letters to His Parent 1939 1864, Appendix I. Canton, MA: Watson – Publishing International; 1989. Schwalbe (1863 1930) published a bibliography of his 5. English PC. Rheumatic Fever in America and Britain. A Biological, teacher’s vast medical writings. This chronological compen- Epidemiological and Medical History. New Brunswick, Canada: Rutgers dium of abstracts summarized each article and book Virchow University Press; 1999. had written. The bibliography was translated into English by 6. Ackerknecht EH. Rudolf Virchow. Doctor, Statesman, Anthropologist. Madison, WI: University of Wisconsin Press; 1953. Leland J. Rather in 1990. He added key annotations and ’ 12 7. Otis L. Müller sLab. Oxford, United kingdom: Oxford University Press; 2007. corrected some minor errors in the original work. The first 8. Bradbury S. The quality of the image produced by the compound entry in Schwalbe’s bibliography was Virchow’s dissertation. microscope: 1700–1840. In: Bradbury S, ed. Historical Aspects of Micros- The abstract explains Virchow’s view of rheumatic keratitis copy. Cambridge, United kingdom: England, W. Heffer & Sons; 1967. as a condition cause by an irritant in the blood, and thus 9. Duke-Elder S, Leigh GA. Diseases of the Outer Eye, Part 2. St Louis, “ ” MO: CV Mosby; 1965. a blood dyscrasia. The abstract goes on to credit Virchow 10. Long ER. A History of Pathology. New York, NY: Dover Publications; 1965. with identifying the cornea as connective tissue. Rather, who 11. Scott A, Khan KM, Cook JL, et al. What is “inflammation”? Are we used his knowledge of modern medicine to enhance appre- ready to move beyond Celsus? Br J Sports Med. 2004;38:248–249. ciation of historical works, included insightful comments on 12. Rather LJ. A Commentary on the Medical Writings of Rudolf Virchow: Based on Schwalbe’s Virchow-Bibliographie, 1843–1901. San Francisco, about a third of the articles Virchow wrote. He did not CA, Norman Pub; 1990. add any additional observations to Schwalbe’s summary of 13. Duke-Elder S, Wybar KC. The Anatomy of the Visual System. Vol. II. St Virchow’s dissertation. Louis, MO: CV Mosby; 1961.