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Modern disease nosology arose in the late nineteenth century and represented a clear departure from the holistic, limited descriptions of disease dating to Galen. In this rubric, the definition of any disease is largely based on clinicopathologic observation. As the correlation between clinical signs and symptoms with pathoanatomy required autopsy material, diseases tended to be characterized by the end organ in which the primary syndrome was manifest and by late-stage presentations. Morgagni institutionalized this framework with the publication of De Sedibus et Causis Morborum per Anatomen Indagatis in 1761, in which he correlated the clinical features of patients with more than 600 autopsies at the University of Padua, demonstrating an anatomic basis for disease pathophysiology. Clinicopathologic observation served as the basis for inductive generalization coupled with the application of Occam’s razor in which disease complexity was reduced to its simplest possible form. While this approach to defining human disease has held sway for over a century and facilitated the conquest of many diseases previously considered incurable, overly inclusive and simplified Oslerian diagnostics suffer from significant shortcomings. These include, but are not limited to, failure to distinguish the underlying etiology of different diseases with common pathophenotypes. For example, many different diseases can cause end-stage kidney disease or heart failure. Over time, the classification of neurodegenerative disorders or lymphomas, as well as many other diseases, is becoming more refined and precise as the underlying etiologies are identified. These distinctions are important for providing predictable prognostic information for individual patients with even highly prevalent diseases. Additionally, therapies may be ineffective owing to a lack of understanding of the often subtle molecular complexities of specific disease drivers.

Beginning in the mid-twentieth century, the era of molecular medicine offered the idealized possibility of identifying the underlying molecular basis of every disease. Using a conventional reductionist paradigm, physician-scientists explored disease mechanism at ever-increasing molecular depth, seeking the single (or limited number of) molecular cause(s) of many human diseases. Yet, as effective as this now conventional scientific approach was at uncovering many disease mechanisms, the clinical manifestations of very few diseases could be explained on the basis of a single molecular mechanism. Even knowledge of the globin β chain mutation that causes sickle cell disease does not predict the many different manifestations of the disease (stroke syndrome, painful crises, and hemolytic crisis, among others). Clearly, the profession had expected too much from oversimplified reductionism and failed to take into consideration the extraordinary biologic variety and its accompanying molecular and genetic complexity that underpin both normal and pathologic diversity. The promise of the Human Genome Project provided new tools and approaches and unleashed efforts to identify a monogenic, oligogenic, or polygenic cause for every disease (allowing for environmental modulation). Yet, once again, disappointment reigned as the pool of genomes expanded without the expected revelations (aside from rare variants). The arc of progressive reductionism (as illustrated for tuberculosis in Fig. 5-1) in ...

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