Editing George Whipple (section)

==Whipple's research==
Over the course of his career, Whipple authored or co-authored more than 300 publications.<ref name=":2" />

Whipple's research interests during his career primarily included [[anemia]] and the [[physiology]] and [[pathology]] of the [[liver]].<ref name=":0" /> But he also researched and made significant contributions to tuberculosis, pancreatitis, chloroform poisoning in animals, the metabolism of bile pigments and iron, the constituents of the bile, and the regeneration of plasma protein, protein metabolism, and the stroma of the [[red blood cell]]s.<ref name=":0" />

One of his first publications described the role of the lungs, lymphatic system, and gastrointestinal tract in the spread of tubercle bacillus causing tuberculosis.<ref name=":2" /> Another one of his early publications described autopsy results from a patient with an accumulation of fatty acids in the walls of the small intestine and lymph nodes.<ref name=":2" /> He named this abnormality lipodystrophia intestinalis (intestinal lipodystrophy),<ref name=":2" /> and correctly pointed to the [[bacteria]]l cause of the lipid deposits, resulting in the disease being named [[Whipple's disease]].<ref name=":5" />

When Whipple first joined [[Johns Hopkins School of Medicine]] as an assistant, he worked under [[William H. Welch]], focusing on the repair and regeneration of [[Hepatocyte|liver cells]].<ref name=":0" /> His research in dogs demonstrated that liver cells had an almost unlimited ability to regenerate.<ref name=":0" /> Through his chloroform liver injury studies, Whipple demonstrated that the liver was the site of [[fibrinogen]] synthesis.<ref name=":2" /> His research elucidated the route by which bile pigments enter circulation and produce jaundice in various parts of the body.<ref name=":0" />

Later, he studied [[bile pigments]] and their production outside the liver by way of bile fistulas at the Hooper Foundation at UC San Francisco.<ref name=":0" /> His interests soon extended to understanding the production of hemoglobin to gain a better understand of how it is metabolized into bile pigments.<ref name=":0" /> Co-authored with Hooper, Whipple published 12 papers, from 1915 to 1917, reporting the following:<ref name=":2" />
* Bile pigment bilirubin was a breakdown product of muscle hemoglobin, though red blood cell [[hemoglobin]] was the major normal source. 
* Bile pigment was not reabsorbed and reused in the production of new red blood cells. 
* The heme moiety of hemoglobin could be converted to bilirubin in both the pleural and peritoneal cavities, in addition to the liver.
* Normal liver function was essential for the excretion of bilirubin.
* The curve of red blood cell regeneration in anemia, as influenced by dietary factors, like sugar, amino acids and starvation.

At the University of Rochester, Whipple's research focus became studying the various factors in diets which contributed to recovery of long-term anemia, particularly in anemic dogs.<ref name=":0" /><ref name=":1" /> Along with his research assistant, [[Frieda Robscheit-Robbins]] (formally Frieda Robbins), they co-authored 21 publications, from 1925 to 1930, reporting the following:<ref name=":0" /><ref name=":2" />
* Circulating plasma and hemoglobin volumes
* The effects of dietary and other factors on [[bile]] salt production and secretion
* Measurements of blood [[fibrinogen]]
* The effects of diet, [[Bleeding|hemorrhage]], liver injury, and other factors on plasma fibrinogen levels
* Blood regeneration following simple anemia
Whipple and Robscheit-Robbins were regarded as having one of the "great creative partnerships in medicine".<ref name=":5" />

In his landmark studies, published as a series "Blood Regeneration in Severe Anemia" beginning in 1925, Whipple demonstrated that raw liver fed to anemic dogs was the most effective diet additive for reversing the anemia by boosting the production of red blood cells.<ref name=":0" /><ref name=":1" /><ref name=":2" /> He would go on to show that foods derived from animal tissue, and cooked apricots also had a positive effect of increasing red blood cells during anemia.<ref name=":2" /> Based on these data, Whipple associated the iron content in these dietary factors to the potency of red blood cell regeneration.<ref name=":2" /> This data led directly to successful liver treatment of [[pernicious anemia]] by [[George Minot|George R. Minot]] and [[William P. Murphy]],<ref name=":6" /> despite the main therapeutic mechanism being through B12 rather than iron.<ref name=":5" /> This was a remarkable discovery since previously, pernicious anemia was invariably fatal at a young age.<ref name=":6" /> For his contribution to this body of work, he was jointly awarded the Nobel Prize in physiology or medicine in 1934 along with Minot and Murphy.<ref name=":0" />

In 1937, Whipple collaborated with William B. Hawkins to determine the life-span of the red blood cell in dogs.<ref name=":2" /> Simultaneously, with the advent of radioactive iron, Whipple, Paul F. Hahn, and William F. Bale collaborated to study iron absorption and utilization.<ref name=":2" /> They demonstrated that iron absorption was highly regulated in the small intestine and was influenced by the amount of iron stores in the body.<ref name=":2" /> They also demonstrated that insignificant amounts of iron were normally excreted or lost in the urine, feces, or bile.<ref name=":2" /> During this time, Whipple also formulated his theory on "the dynamic equilibrium between blood and tissue proteins" based on earlier plasmapheresis experiments he had performed (in the early 1930s) which demonstrated the importance of dietary protein on production of plasma proteins.<ref name=":2" /> This formed the foundation of research into mammalian protein metabolism, and led [[Rudolph Schoenheimer|Rudolf Schoenheimer]] to write ''The Dynamic State of the Body Constituents,'' marking the modern era of biochemistry and biology.<ref name=":2" />

Between 1939 and 1943 Leon L. Miller and Whipple collaborated to study the hepato-toxic effects of chloroform anesthesia on dogs.<ref name=":2" /> They found that dogs in a protein depleted state sustained lethal liver injury from within anesthesia fifteen minutes; but that feeding these depleted dogs a protein rich meal, particularly rich in L-methionine or L-cystine, prior to anesthesia was protective.<ref name=":2" /> This and other studies, led Whipple to the conclusion that S-containing amino acids are protective against liver against toxic agents.<ref name=":2" />

During World War II, Whipple tested combinations of dietary amino acids, administered, orally or parenterally, and their effects on plasma protein synthesis.<ref name=":2" /> He was able to characterize [[amino acid]] mixtures that could satisfy the metabolic requirements necessary to maintain weight, nitrogen balance, and plasma protein and hemoglobin regeneration in the dog.<ref name=":2" /> This would ultimately led to human clinical trials which demonstrated that these amino acid mixtures, along with enzymatic digest of casein, could sustain nourishment in patients who could not intake nutrients through the normal gastrointestinal route for extended periods.<ref name=":2" /> Intravenous nutrition, referred to as [[parenteral nutrition]], is routinely used today.<ref name=":2" />