We trace the history of our subject to the date when the man who many regard as its founder, Rudolf Ludwig Karl Virchow, who, building on the work of Theodore Schwann 1, enunciated the cell theory, omnis cellula e cellula (each cell stems from another cell), and which arguably led to the concept of cellular pathology 2. Now, whether he did or not is a moot question: in fact there is evidence that he plagiarized the work of Robert Remak, who first discovered that the origin of cells was by the division of pre-existing cells 3. Even his famous epigram may not be his own: it was in fact first coined by François-Vincent Raspail 4. That apart, he obviously did a good job, particularly in the public relations field.
The present Annual Review Issue of The Journal of Pathology, published some 150 years after Virchow's seminal book Cellular Pathology2, underlines its importance: the processes of what we now call cell biology make up the foundation of our understanding of the mechanisms of disease. Naturally, with the elucidation of the human genome, and the growing ability to analyse whole human genomes, our knowledge of the molecular aberrations responsible for even genetically complex diseases is growing exponentially. But the identification of mutant genes or changes in the patterns of gene expression, while critical, is not sufficient to increase understanding of the mechanisms of disease. We need to understand the context-dependent functions, often also cell-lineage specific, of these many gene products, and to develop assays which make their analysis possible. It's a very reasonable bet that the growing revolution in genomics and bioinformatics will lead to a heavy dependence on cell biology, and of course cell biologists. So, in this Annual Review Issue we have indeed collected a pantheon of leading cell biologists whose work impinges directly on important disease mechanisms.
Cell–cell communication via chemokines is important in controlling the movement of multiple cell types and their role in malignancy because chemokines (and their receptors) control cell trafficking within the tumour microenvironment, contribute to the nature of the myeloid component of the tumour stroma, to angiogenesis, and the makeup of the myofibroblast/fibroblast stroma 5. Disruption of cell–cell connectivity, which mediates adherence and communication, particularly of desmosomes, results in severe pathology, particularly in the skin 6. Christensen and colleagues trace the revolution in our knowledge of the function of primary cilia in the coordination of signal transduction pathways affecting entrance into the cell cycle, cell migration, and differentiation in developmental homeostasis 7.
Cells have an intimate relationship with their surroundings, and interactions with the extracellular matrix are pivotal in maintaining tissue homeostasis: the corollary is that this relationship is similarly important in pathogenesis. Thus, the different scaffolds found in various tissues promote or indeed prevent invasion by malignant cells, where physical guidance is complemented by molecular guidance by integrins, chemokines, and growth factors 8. The biological importance of extracellular matrix–cell membrane–cytoskeleton interactions in skeletal muscle is underlined by inherited muscle diseases caused by mutations in genes encoding extracellular matrix proteins such as laminins, collagens, dystroglycan, integrins, dystrophin, and sarcoglycans inducing various forms of muscular dystrophy 9. In cartilage, chondrocyte–matrix interactions compensate for the lack of cell–cell contact. Proteoglycans and other molecules fulfil this role, and also establish gradients which regulate the epiphyseal growth plate; mutations in genes that control cell–matrix interactions can contribute to loss of cell polarity and the development of osteochondromas and consequent secondary peripheral chondrosarcomas 10. There has been a resurgence of interest in epithelio-mesenchymal transition, with the recent controversial proposal that this change must occur before neoplastic epithelial cells can invade: disturbance of mesenchymal to epithelial transition is also associated with a number of developmental abnormalities. It is therefore not surprising that WT1 has been linked to many of these. While WT1 behaves as a classic tumour suppressor gene in Wilms' tumours, it also controls transitions between the mesenchymal and epithelial state of cells and is involved in the control of the mesenchymal–epithelial balance of cells in a variety of disease states 11.
Several organelles are of particular interest in the development of disease: using the paradigm of storage diseases, Cox and Cachón González explore the role of the lysosome, through the finding of disordered autophagy and the generation of toxic metabolites to the exciting prospect of the development of new therapy for Gaucher disease 12. This reflects the surge of interest in autophagy itself 13, where its importance in the maintenance of cellular homeostasis, energy balance, and cellular and tissue remodelling in cellular defence is now recognized, and also that defects in autophagy are involved in several pathological processes. It is now very clear that mutations in mitochondrial DNA are a relatively common cause of inherited disease. With a focus on adult neurological disease, Greaves and colleagues examine the role of mitochondrial DNA mutations in neurodegenerative diseases, ageing, and cancer 14. Recent data also indicate that the septins, a family of GTP binding proteins, play a formidable and more direct role in stabilization of membranes by directly binding and modifying membranes; also their role in defining spatial asymmetry and cell polarity is becoming clearer, as is their contribution to disease 15. ATP-binding cassette transporters are ubiquitous integral membrane proteins that actively transport ligands across biological membranes. Their dysfunction underlies a number of human genetic diseases, particularly cholestatic disorders, and also underpins resistance to antibiotics and chemotherapeutic drugs 16.
Turning to the nucleus, mutations in the nuclear lamins, long known to be essential for the maintenance of the nuclear lamina, have been shown to cause a range of lesions in striated muscle, adipose, and peripheral nerve—the laminopathies, and recently model organisms have pointed the way towards treatments 17. In Fanconi anaemia, there is stem cell loss causing progressive bone marrow failure and predisposition to neoplasia. Recent work has identified a specific component of the Fanconi anaemia pathway that regulates nucleases involved in DNA interstrand crosslink repair 18. Most mammalian somatic cells are diploid, but polyploidy results from cytokinesis failure. While polyploidy is essential for cellular differentiation and function in lineages such as hepatocytes and megakaryocytes, failure or dysregulation of cytokinesis has dire consequences 19. That deregulation of the cell cycle causes the increased cell proliferation found in cancer and that loss of cell cycle checkpoint control promotes genetic instability have become truisms, but using these to identify prognostic and therapeutic tools remains challenging. However, recent studies of the DNA replication initiation machinery and mitotic engine proteins in human tissues have led to the development of novel biomarkers for both prognosis and possible therapy 20. While synthetic nucleic acids such as antisense oligonucleotides and small interfering RNAs are in widespread use for modulating gene expression in the laboratory, their potential in treatments and factors affecting their action are now becoming apparent 21.
Cell detachment from the matrix, disrupting integrin binding, induces a form of programmed cell death—anoikis. Preventing detached epithelial cells from colonizing is essential for tissue homeostasis. The molecular mechanisms controlling this process are now becoming clearer, and its role in neoplasia and epithelial–mesenchymal transition defined 22. Notch signalling regulates development and tissue homeo-stasis in many tissues including the kidney, where Notch helps to establish proximal epithelial fate and differentiation the renal collecting duct system. But Notch signalling has also been associated with proteinuria and glomerulosclerosis, and in tubules with fibrosis 23. Downstream signalling of growth factor receptors and integrins converge on the non-receptor tyrosine kinase Focal Adhesion Kinase, deeply involved in endothelial cell biology, and a recent focus of attention in the control of tumour angiogenesis, long known to be essential for tumour development 24.
Virchow did not, at first, believe in cell division but apparently had a Damascene conversion and he re-published Remak's work as his own. Understandably this caused somewhat of a rift between them 25. However, if Virchow and Remak, together with François-Vincent Raspail, are looking down from some pathological Valhalla, I think they will be well pleased with the results of the revolution in pathology they set in train.