Editing Pathophysiology (section)

====Molecular paradigm====

The [[1918 pandemic]] triggered frenzied search for its cause, although most deaths were via [[lobar pneumonia]], already attributed to [[pneumococcus|pneumococcal]] invasion.  In London, pathologist with the Ministry of Health, [[Fred Griffith]] in 1928 reported pneumococcal [[bacterial transformation|transformation]] from virulent to avirulent and between antigenic types —nearly a switch in species— challenging pneumonia's specific causation.<ref>"In the bacteriology of the 1920s, the conversion of the R to the S form could be regarded as an adaptation to the environment. However, the transformation of Type I to Type II was the equivalent of the transformation of one species into another, a phenomenon never before observed.  Avery was initially skeptical of Griffith's findings and for some time refused to accept the validity of his claims, believing that they were the result of inadequate experimental controls. Avery's research on therapeutic sera led him to conclude that pneumococcal types were fixed and that specific therapeutic agents could thus be developed to combat the various types. A transformation from type to type [[in vivo]] presented a disturbing clinical picture, as well as a challenge to the theoretical formulations of contemporary bacteriology" [Oswald T Avery Collection, [http://profiles.nlm.nih.gov/ps/retrieve/Narrative/CC/p-nid/38 "Shifting focus: Early work on bacterial transformation, 1928-1940"], ''Profiles in Science'', US National Library of Medicine, Web: 24 Jan 2013].</ref><ref>[[René Dubos|Dubos, René J]], [http://profiles.nlm.nih.gov/ps/access/CCAAOG.ocr ''Oswald T Avery: His Life and Scientific Achievements''] (New York: Rockefeller University Press, 1976), pp 133, 135-136</ref> The laboratory of Rockefeller Institute's [[Oswald T. Avery|Oswald Avery]], America's leading pneumococcal expert, was so troubled by the report that they refused to attempt repetition.<ref name=Dubos>Dubos, René, [http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/CCAAOA "Memories of working in Oswald Avery's laboratory"], Symposium Celebrating the Thirty-Fifth Anniversary of the Publication of "Studies on the chemical nature of the substance inducing transformation of pneumococcal types", 2 Feb 1979</ref>

When Avery was away on summer vacation, [[Martin Henry Dawson|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.<ref name=Dubos/> Having returned, Avery kept a photo of Griffith on his desk while his researchers followed the trail.  In 1944, Avery, [[Colin Munro MacLeod|Colin MacLeod]], and [[Maclyn McCarty]] reported the transformation factor as [[DNA]], widely doubted amid estimations that something must act with it.<ref>{{cite journal | author = Lederberg J | year = 1956 | title = Notes on the biological interpretation of Fred Griffith's finding | url = http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/CCAAQX | journal = American Scientist | volume = 44 | issue = 3| pages = 268–269 }}</ref>  At the time of Griffith's report, it was unrecognized that bacteria even had genes.<ref>{{cite journal | author = Lacks SA | title = Rambling and scrambling in bacterial transformation—a historical and personal memoir | journal = J Bacteriol | volume = 185 | issue = 1 | pages = 1–6 | date = Jan 2003 | pmid = 12486033 | doi = 10.1128/jb.185.1.1-6.2003 | pmc=141969}}</ref>

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.<ref name=Bechtel>Bechtel, William, [https://books.google.com/books/about/Discovering_Cell_Mechanisms.html?id=WrEquK3hoDwC ''Discovering Cell Mechanisms: The Creation of Modern Cell Biology''] (New York: Cambridge University Press, 2005)</ref> In the 1940s, most scientists viewed the cell as a "sack of chemicals" —a membrane containing only loose molecules in [[Brownian motion|chaotic motion]]— and the only especial cell structures as chromosomes, which bacteria lack as such.<ref name=Bechtel/>  Chromosomal DNA was presumed too simple, so genes were sought in [[histones|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, [[Francis Crick|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]].<ref>Kay, Lily, [https://books.google.com/books?id=vEHeNI2a8OEC ''Molecular Vision of Life: Caltech, the Rockefeller Foundation, and the Rise of the New Biology''] (New York: Oxford University Press, 1993)</ref>  Yet the reality of [[organelles]] in cells was controversial amid unclear visualization with conventional [[light microscopy]].<ref name=Bechtel/>  Around 1940, largely via cancer research at Rockefeller Institute, [[cell biology]] emerged as a new discipline filling the vast gap between [[Cytopathology|cytology]] and [[biochemistry]] by applying new technology —[[ultracentrifuge]] and [[electron microscope]]— to identify and deconstruct cell structures, functions, and mechanisms.<ref name=Bechtel/>  The two new sciences interlaced, ''cell and molecular biology''.<ref name=Bechtel/>

Mindful of [[Fred Griffith|Griffith]] and [[Oswald T. Avery|Avery]], [[Joshua Lederberg]] confirmed [[bacterial conjugation]] —reported decades earlier but controversial— and was awarded the 1958 [[Nobel Prize in Physiology or Medicine]].<ref name=IOM2009>{{cite book |author=[[Institute of Medicine]] Forum on Microbial Threats |title=Microbial Evolution and Co-Adaptation: A Tribute to the Life and Scientific Legacies of Joshua Lederberg: Workshop Summary |location=Washington DC |publisher=National Academies Press |year=2009 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK45705 |chapter=The Life and Legacies of Joshua Lederberg |isbn=978-0-309-13121-6}}</ref>   At [[Cold Spring Harbor Laboratory]] in Long Island, New York, [[Max Delbrück|Delbrück]] and [[Salvador Luria]] led the [[Phage Group]] —hosting [[James Watson|Watson]]— discovering details of cell physiology by tracking changes to bacteria upon infection with [[bacteriophage|their viruses]], the process [[transduction (genetics)|transduction]].  Lederberg led the opening of a genetics department at [[Stanford University]]'s medical school, and facilitated greater communication between biologists and medical departments.<ref name=IOM2009/>