Pathophysiology

History

The term pathophysiology comes from the Ancient Greek πάθος (pathos) and φυσιολογία (phusiologia).

Reductionism

In Germany in the 1830s, Johannes Müller led the establishment of physiology research autonomous from medical research. In 1843, the Berlin Physical Society was founded in part to purge biology and medicine of vitalism, and in 1847 Hermann von Helmholtz, who joined the Society in 1845, published the paper "On the conservation of energy", highly influential to reduce physiology's research foundation to physical sciences. In the late 1850s, German anatomical pathologist Rudolf Virchow, a former student of Müller, directed focus to the cell, establishing cytology as the focus of physiological research, while Julius Cohnheim pioneered experimental pathology in medical schools' scientific laboratories.

Germ theory

By 1863, motivated by Louis Pasteur's report on fermentation to butyric acid, fellow Frenchman Casimir Davaine identified a microorganism as the crucial causal agent of the cattle disease anthrax, but its routinely vanishing from blood left other scientists inferring it a mere byproduct of putrefaction. In 1876, upon Ferdinand Cohn's report of a tiny spore stage of a bacterial species, the fellow German Robert Koch isolated Davaine's bacterides in pure culture—a pivotal step that would establish bacteriology as a distinct discipline—identified a spore stage, applied Jakob Henle's postulates, and confirmed Davaine's conclusion, a major feat for experimental pathology. Pasteur and colleagues followed up with ecological investigations confirming its role in the natural environment via spores in soil.

Also, as to septicemia, Davaine had injected rabbits with a highly diluted, tiny amount of putrid blood, duplicated disease, and used the term ferment of putrefaction, but it was unclear whether this referred as did Pasteur's term ferment to a microorganism or, as it did for many others, to a chemical. In 1878, Koch published Aetiology of Traumatic Infective Diseases, unlike any previous work, where in 80 pages Koch, as noted by an historian, "was able to show, in a manner practically conclusive, that a number of diseases, differing clinically, anatomically, and in aetiology, can be produced experimentally by the injection of putrid materials into animals." Koch used bacteriology and the new staining methods with aniline dyes to identify particular microorganisms for each. Germ theory of disease crystallized the concept of etiology—a disease's specific causation—presumably identifiable by scientific investigation.

Scientific medicine

The American physician William Welch trained in German pathology from 1876 to 1878, including under Cohnheim, and opened America's first scientific laboratory—a pathology laboratory—at Bellevue Hospital in New York City in 1878. Welch's course drew enrollment from students at other medical schools, which responded by opening their own pathology laboratories. Once appointed by Daniel Coit Gilman, upon advice by John Shaw Billings, as founding dean of the medical school of the newly forming Johns Hopkins University that Gilman, as its first president, was planning, Welch traveled again to Germany for training in Koch's bacteriology in 1883. Welch returned to America but moved to Baltimore, eager to overhaul American medicine, while blending Vichow's anatomical pathology, Cohnheim's experimental pathology, and Koch's bacteriology. Hopkins medical school, led by the "Four Horsemen"—Welch, William Osler, Howard Kelly, and William Halsted—opened at last in 1893 as America's first medical school devoted to teaching German scientific medicine, so called.

Biomedicine

The first biomedical institutes, Pasteur Institute and Berlin Institute for Infectious Diseases, whose first directors were Pasteur and Koch, were founded in 1888 and 1891, respectively. America's first biomedical institute, The Rockefeller Institute for Medical Research, was founded in 1901 with Welch, nicknamed "dean of American medicine", as its scientific director, who appointed his former Hopkins student Simon Flexner as director of pathology and bacteriology laboratories. By way of World War I and World War II, Rockefeller Institute became the globe's leader in biomedical research.

Molecular paradigm

The 1918 pandemic triggered frenzied search for its cause, although most deaths were via lobar pneumonia, already attributed to pneumococcal invasion. In London, pathologist with the Ministry of Health, Fred Griffith in 1928 reported pneumococcal transformation from virulent to avirulent and between antigenic types—nearly a switch in species—challenging pneumonia's specific causation. The laboratory of Rockefeller Institute's Oswald Avery, America's leading pneumococcal expert, was so troubled by the report that they refused to attempt repetition.

When Avery was away on summer vacation, Martin Dawson, British-Canadian, convinced that anything from England must be correct, repeated Griffith's results, then achieved transformation in vitro, too, opening it to precise investigation. Having returned, Avery kept a photo of Griffith on his desk while his researchers followed the trail. In 1944, Avery, Colin MacLeod, and Maclyn McCarty reported the transformation factor as DNA, widely doubted amid estimations that something must act with it. At the time of Griffith's report, it was unrecognized that bacteria even had genes.

The first genetics, Mendelian genetics, began at 1900, yet inheritance of Mendelian traits was localized to chromosomes by 1903, thus chromosomal genetics. Biochemistry emerged in the same decade. In the 1940s, most scientists viewed the cell as a "sack of chemicals"—a membrane containing only loose molecules in chaotic motion—and the only especial cell structures as chromosomes, which bacteria lack as such. Chromosomal DNA was presumed too simple, so genes were sought in chromosomal proteins. Yet in 1953, American biologist James Watson, British physicist Francis Crick, and British chemist Rosalind Franklin inferred DNA's molecular structure—a double helix—and conjectured it to spell a code. In the early 1960s, Crick helped crack a genetic code in DNA, thus establishing molecular genetics.

In the late 1930s, Rockefeller Foundation had spearheaded and funded the molecular biology research program—seeking fundamental explanation of organisms and life—led largely by physicist Max Delbrück at Caltech and Vanderbilt University. Yet the reality of organelles in cells was controversial amid unclear visualization with conventional light microscopy. Around 1940, largely via cancer research at Rockefeller Institute, cell biology emerged as a new discipline filling the vast gap between cytology and biochemistry by applying new technology—ultracentrifuge and electron microscope—to identify and deconstruct cell structures, functions, and mechanisms. The two new sciences interlaced, cell and molecular biology.

Mindful of Griffith and Avery, Joshua Lederberg confirmed bacterial conjugation—reported decades earlier but controversial—and was awarded the 1958 Nobel Prize in Physiology or Medicine. At Cold Spring Harbor Laboratory in Long Island, New York, Delbrück and Salvador Luria led the Phage Group—hosting Watson—discovering details of cell physiology by tracking changes to bacteria upon infection with their viruses, the process transduction. Lederberg led the opening of a genetics department at Stanford University's medical school, and facilitated greater communication between biologists and medical departments.

Disease mechanisms

In the 1950s, researches on rheumatic fever, a complication of streptococcal infections, revealed it was mediated by the host's own immune response, stirring investigation by pathologist Lewis Thomas that led to identification of enzymes released by the innate immune cells macrophages and that degrade host tissue. In the late 1970s, as president of Memorial Sloan–Kettering Cancer Center, Thomas collaborated with Lederberg, soon to become president of Rockefeller University, to redirect the funding focus of the US National Institutes of Health toward basic research into the mechanisms operating during disease processes, which at the time medical scientists were all but wholly ignorant of, as biologists had scarcely taken interest in disease mechanisms. Thomas became for American basic researchers a patron saint.

Uses

Pathophysiology is a required area of study for nearly all healthcare professional school programs (medical, dental, physician assistant, occupational therapy, physical therapy, nurse practitioner, radiation therapists, pharmacy, nursing, radiologic science, Chiropractic and paramedic programs) in the United States, Canada and other countries.