Analytical Biochemistry: the Work of Otto Knuf Olof Folin on Blood Analysis

A System of Blood Analysis (Folin, O., and Wu, H. (1919) J. Biol. Chem. 38, 81–110) Otto Knut Olof Folin was born in Sweden, but at age 15 he was sent by his parents to Minnesota to join two brothers and an aunt. He attended the University of Minnesota and subsequently received a Ph.D. degree from the University of Chicago (1Shaffer P.A. Obituary of Stanley Rossiter Benedict.J. Biol. Chem. 1937; 117: 428Google Scholar). After a time in Europe learning physiological chemistry, he was employed as a research biochemist at McLean Hospital (for the Insane) in Waverly, Massachusetts. He was charged with comparing the composition of urine from normal and insane people. He realized that to do this in a meaningful way required new analytical approaches to urinalysis. In 1905, Folin published three papers in the American Journal of Physiology (2Folin O. Approximately complete analysis of thirty “normal” urines.Am. J. Physiol. 1905; 13 (32): 45Crossref Google Scholar, 3Folin O. Laws governing the chemical composition of urine.Am. J. Physiol. 1905; 13 (32): 66Crossref Google Scholar, 4Folin O. A theory of protein metabolism.J. Am. Physiol. 1905; 13: 117-132Crossref Google Scholar) which, according to E. V. McCollum, “marked a turning point in the history of biochemistry” and “immediately brought him distinction” (1Shaffer P.A. Obituary of Stanley Rossiter Benedict.J. Biol. Chem. 1937; 117: 428Google Scholar). These papers reported methods for analysis of urine for urea, ammonia, creatine, creatinine, and uric acid, the major non-protein nitrogen-containing compounds in urine. Unlike previous analytical methods for these compounds, Folin's methods were relatively specific and sensitive so that small sample volumes were adequate. His research was very highly regarded, and in 1907, a professorship in biochemistry was created at Harvard Medical School where he served until his death in 1934 (5Chittenden R.H. The First Twenty-five Years of the American Society of Biological Chemists. Williams & Wilkins, Baltimore, MD1945Google Scholar). Folin's work stimulated laboratories around the world to approach the study of urine samples as a way to understand normal and pathological physiological processes. The work also stimulated experiments on animals treated in ways to mimic disease states. Folin turned his attention to applying his analytical methods, developed for urinalysis, to the analysis of blood. He was probably the first, as McCollum states, “to realize that it is much more important to know what the kidneys have failed to excrete, among the products of metabolic activity of the body, and which products accordingly, accumulate to harmful concentrations in the blood, than it is to know what and how much of these have cleared the kidneys” (1Shaffer P.A. Obituary of Stanley Rossiter Benedict.J. Biol. Chem. 1937; 117: 428Google Scholar). Folin's work, including the paper reprinted in this installment of the Journal of Biological Chemistry (JBC) Classics, represents several“ firsts” in biochemistry: the systematic development of“ micromethods”; the use of colorimetry in biochemistry, the Duboscq colorimeter; and the use of an enzyme for analytical purposes, urease to measure urea. This paper is a model of the Folin approach to biochemistry with very careful detail and accuracy. Among many lasting contributions, Folin, with Vintila Ciocalteu, developed the “Phenol Reagent” for use in protein determinations (6Folin O. Ciocalteu V. On tyrosine and tryptophane determinations in proteins.J. Biol. Chem. 1927; 73: 627Abstract Full Text PDF Google Scholar). This reagent is the basis of the Lowry method for protein determination, which is the most highly cited paper in science (7Lowry O.H. Rosebrough N.J. Farr A.L. Randall R.J. Protein measurement with the Folin Phenol Reagent.J. Biol. Chem. 1951; 193 (232): 265Abstract Full Text PDF PubMed Google Scholar, 8Shaffer P.A. Biographical Memoir of Otto Folin. National Academy of Sciences Biographical Memoirs. 27. National Academy of Sciences, Washington, D. C.1927: 47Google Scholar). The Folin-Ciocalteu paper will be reprinted with the Lowry paper in a future installment of JBC Classics and is itself a “Classic.” The same can be said for an advertisement for the Duboscq colorimeter, which we are also reprinting here. As described by McCollum in his obituary for Stanley R. Benedict (1Shaffer P.A. Obituary of Stanley Rossiter Benedict.J. Biol. Chem. 1937; 117: 428Google Scholar), Benedict and Folin had parallel careers and common interests in analytical biochemistry/clinical chemistry and disagreed on many scientific issues. On this point, Benedict wrote of Folin soon after his death. “One of the qualities which so impressed me of Folin, so rare among scientific workers, was the fact that he was able to drop out personalities when it came to a matter of difference of scientific opinion. I have known no one with whom it was possible to have such a strenuous difference of opinion or viewpoint in scientific work and have this not interfere one iota in the close personal relationship which lasted for more than twenty-five years.” In 1919, Folin was the third President of the American Society of Biological Chemists (ASBC) and was a member of the JBC Editorial Board for more than 25 years starting with the first issue in 1905 (5Chittenden R.H. The First Twenty-five Years of the American Society of Biological Chemists. Williams & Wilkins, Baltimore, MD1945Google Scholar).