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DNA Pioneers and Their Legacy by Ulf Lagerkvist, 1998, Yale University Press, ISBN 0-300-07184-1

In this entertaining account of the origins of modern molecular biology, the lives of pioneering scientists in the field of nucleic acid research, and of the discovery of DNA, Ulf Lagerkvist speaks not only to scientists but to all students and general readers with an interest in science. The author, whose career in the nucleic acid field began in the late 1940's. re-creates historical episodes from the nineteenth and early twentieth centuries....Among these scientific pioneers was the nineteenth-century biochemist Friedrich Miescher, discoverer of nuclein, the material now known as DNA...


"In the year 1844 the city of Basel was still suffering from the separation of the town from the surrounding rural half-canton Basel-Land, which had revolted against the domination of Basel in 1831 and obtained its independent status in 1833. Working conditions were far from ideal at the university, founded in 1460 by Pope Pius II. Yet it could boast such luminaries as Erasmus among its long row of famous past scholars."

"From an early age Friedrich was recognized as being highly intelligent, but he was shy and introspective - perhaps in part as the result of a serious hearing impairment he had suffered from since boyhood. Despite this handicap he took great interest in music, something he had in common with his father, a talented singer who gave public concerts. Not unexpectedly, Friedrich did very well at school."

"It may be of interest to consider for a moment the general situation of contemporary medicine when Miescher took up his medical studies. The basic sciences of medicine - anatomy, pathology, physiology, and biochemistry - had made enormous progress. When scientifically based clinical research slowly emerged in the first decades of the nineteenth century, however, the practice of medicine was in a state of bankruptcy. Not only was the intellectual framework, based on the body humors that had ruled medical thinking for two millennia, in chaos and disintegration, but even venesection (bloodletting), the unshakable foundation of all therapy, was being questioned."

"In 1865, while he was still a medical student, Miescher went to Goettingen for the summer in order to work in the laboratory of the organic chemist Adolf Strecker. On his return to Basel he contracted typhoid fever and to interrupt his studies for almost a year. Nevertheless, he got his M.D. in 1868 and considered what field in medicine he should enter.
Friedrich Miescher then did something that would surely boggle the mind of any physician of our time. He wrote a long letter, or rather an extensive essay, to his father in which he set out his thoughts about his own future and carefully weighed the pros and cons of his various options. Even the effects of his hearing impairment were thoroughly considered, for this was a serious handicap indeed for a clinician"

"Miescher had originally intented to study lymphocytes, but he soon realized that it would be impossible to get enough of these cells. Encouraged by Hoppe-Seyler, he instead focussed on leucocytes, known to be the main cellular constituent of the laudable pus that could be obtained fresh every day from used bandages in the nearby hospital. The trick was to wash the cells without damaging them. To this end Friedrich tried various salt solutions, but the cells swelled and gave rise to a highly viscous porridge that was impossible to handle. In hindsight it is easy to see that this occurred because he extracted high-molecular-weight DNA from damaged cells. Eventually he hit on a dilute solution of sodium sulfate as the best way to rinse well-preserved cells from the bandages. After filtration to get rid of tissue fibers, the cells were left to sediment to the bottom of the beaker; laboratory centrifuges were nonexistent in those days. When examined in the microscope, the leucocytes seemed intact and showed no sign of damage."

"His first task was to isolate undamaged nuclei free of cytoplasm. This had never been accomplished before and only after long hours of hard work did Miescher come up with reasonable quantities of nuclei in good condition. He tried several methods, but his final procedure was as follows. Miescher first treated the cells with warm alcohol to remove lipids, then digested away the proteins of the cytoplasm with the proteolytic enzyme pepsin. What he used was not a pure preparation of crystalline pepsin, as would be used today; nothing comparable was available. Instead, he extracted pig's stomach with dilute hydrochloric acid, which gave hime an active but highly impure enzyme that he used for his digestions. The pepsin treatment solubilized the cytoplasm and left the cell nuclei behind as greyish precipitate...
He subjected his purified nuclei to the same alkaline extraction procedure he had previousely used with the whole cells, and on acidification he again obtained a precipitate. Obviously this material must have come from the nucleus, and he therefore named it nuclein. Using elemetary analysis, one of the few methods available to characterize an unknown compound. Miescher found that his new substance contained 14 percent nitrogen, 3 percent phosphorus, and 2 percent sulfur. Its comparatively high phosphorus content and its resistance to digestion with pepsin suggested that the substance was not a protein. (At the same time, its appreciable content of sulfur immediately indicates to us today that his preparation did contain sustantial amounts of proteins.)"

Miescher Friedrich. "Ueber die chemische Zusammensetzung der Eiterzellen." Hoppe-Seyler's medicinisch-chemische Untersuchungen4 (1871): 441-460
Miescher Friedrich. "Die Spermatozoen einiger Wirbeltiere." Verhandlungen der Naturforschenden Gesellschaft in Basel 6 (1874): 138-208