Reflections

Science in the cultural context

The Isolation of o

First Principles in Science and Ethics
Within the infant rind of this small flower Poison hath residence, medicine power… Shakespeare, Romeo and Juliet

T

he isolation of morphine from opium—the first isolation of a natural product—was a seminal event in the development of pharmacology as an independent discipline. The purification kick-started natural product chemistry and quickly led to the isolation of a host of other alkaloids (Table 1). Within a few years, in 1827, Heinrich Emanuel Merck of Darmstadt began selling morphine, resulting in the development of the eponymous company. A young German pharmacist, Friedrich Wilhelm Adam Sertürner, achieved the purification of morphine. Sertürner was born in Neuhaus, near Paderborn, on June 19, 1783, and died in Hameln on February 20, 1841. His work on opium developed over many years, resulting in some confusion as to the dates of his discovery. The first edition of Goodman & Gilman (1), for example, reports, “In 1805, a young German pharmacist in Hanover named Sertürner isolated and described morphine. This epochal finding went unnoticed until his later publication in 1816. Sertürner almost lost his life by experimenting with morphine on himself.” The second edition (2) states, “In 1803, a young German pharmacist in Paderborn named Sertürner isolated and described morphine,” and in the seventh edition (3) we read, “In 1806, Sertürner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams.” Sertürner did, in fact, begin publishing on opium in Paderborn in 1805 (4), and claims to have begun work before a paper on opium by Derosne had appeared in 1804. This claim has been interpreted to mean that Sertürner began work in 1803. However, his earlier work fixated on acid constituents of opium. Thus, his 1806 paper (5) is mainly concerned with the constituent we now know as meconic acid. He also

TABLE 1. ISOLATION
Year 1817 1818 1818 1819 1820 1820 1822 1827 1828 1831 1832 1833 1833 1842 1848 1851 1860 1870 Compound Narcotine Strychnine Veratrine Colchicine Caffeine Quinine Emetine Coniine Nicotine Aconitine Codeine Atropine Thebaine Theobromine Papaverine Choline Cocaine Muscarine

OF ALKALOIDS

Investigator Robiquet Caventou & Pelletier Meissner & Caventou Meissner & Caventou Runge; Caventou & Pelletier Caventou & Pelletier Pelletier & Magendie Giesecke; Geiger & Hess Posselt & Reimann Mein; Geiger & Hess Robiquet Geiger & Hess Pelletier & Dumas Woskresenky Merck Babo & Hirschbrunn Niemann Schmiedeberg & Koppe

prepared an aqueous alcoholic extraction of opium that had a “sleep-inducing principle.” The extract was tested on four dogs and a mouse that he found wandering in the laboratory. He gave 6 grains to a dog, followed an hour later by another 6 grains. The total dose, therefore, was around 780 milligrams. The dogs vomited, had convulsions, and were drowsy, but did not sleep. One “gentle little dog” died. Because these doses of his extract did not cause sleep, we can conclude that the material was highly impure.
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Reflections

Sertürner moved to Einbeck, just north of Göttingen, in 1806. It was only in 1817, while there, that he unequivocally reported the isolation of pure morphine (6). He prepared it by extracting opium with hot water and precipitating morphine with ammonia. He obtained colorless crystals, poorly soluble in water, but soluble in acids and alcohol. In order to establish that his crystals carried the pharmacological activity of raw opium, Sertürner tested them on himself and three boys, “none older than seventeen.” It was a near-catastrophe. He writes: In order to test my earlier experiments strictly, I encouraged three persons, none older than seventeen years, to take morphine with me simultaneously. Warned by the previous effects, however, I merely administered half a grain dissolved in half a drachma of alcohol and diluted with several ounces of distilled water.1 This produced a generalized redness of cheeks and eyes [perhaps due to the alcohol] and the vital functions appeared generally enhanced. After half an hour, another half-grain was taken; the condition was aggravated markedly, while a transient tendency to vomiting and a dull pain in the head with narcosis was felt. After another 15 minutes, we swallowed another half-grain of morphium, undissolved, as a coarse powder, with 10 drops of alcohol and a half-ounce of water. The outcome with the three young men was decidedly rapid and extreme. It presented as pain in the region of the stomach, exhaustion, and severe narcosis that came close to fainting. I also was subject to the same fate. Being in the supine position, I fell into a dream-like state and sensed in the extremities, particularly the arms, a slight twitching which accompanied the pulse beats. These distinct symptoms of true intoxication, particularly the frail condition of the three young men, caused me so much concern that I, half unconscious, drank more than a quarter of a bottle (6 to 8 ounces) of strong vinegar and also had the others do the same. This led to such severe vomiting that, several hours later, one who was of a particularly delicate constitution and whose stomach had already been emptied completely, found himself in a continuous state of a most painful and highly alarming retching. In this condition, I gave him carbonated magnesia, upon which the vomiting subsided instantly. The night passed under deep sleep. Although the vomiting recurred in the morning, it immediately subsided after a strong dose of magnesia. Lack of opening of the body, loss of appetite,
1

narcosis, and pain in the head and body disappeared only after several days. Judging from these highly unpleasant experiences, I deduce that morphine, even in small quantities, acts as a strong poison. . . . As none of the other components of opium possesses effects such as those described here, the important medicinal properties of opium probably result from pure morphine, which I have to leave to the physicians to test. In this and other experiments, Sertürner showed that his crystalline material had the pharmacological actions of opium by testing it both on animals and humans. Importantly, he also demonstrated that other preparations from opium were devoid of activity. As a consequence of his studies, Sertürner established the principle that plants contain active substances that, on isolation, carry the therapeutic properties of the plant. Sertürner further concluded that morphine would soon replace opium. We are left feeling uneasy about the experiment on the teenaged boys. Although scientifically important, the experiment is ethically dubious. Sertürner was not a physician and also took part in the experiment, with a near-disastrous loss of judgment as a result. A modern Human Subjects Committee would not approve. Indeed, such an experiment today would open the investigator to criminal prosecution. Was Sertürner’s experiment acceptable by 1817 standards? There should perhaps have been a physician present who was not an experimental subject. If the experiment was morally or ethically reprehensible, the transgression is insignificant compared to the slaughters being wrought by Napoleon. One has only to think of the 200 amputations carried out (without anesthesia) in one day by the French army surgeon, Larrey, at the battle of Borodino, to place Sertürner’s experiments in context. However, other experiments on humans in Germany, a century or more in the future, would reach back to shadow reflections on Sertürner’s achievement. Claims of priority in the discovery of morphine have been made for two other investigators. Jean-Francois Derosne (8) prepared a crude extract of opium (with alcohol and water), and obtained, by potassium carbonate precipitation, what he called “sel de Derosne.” Derosne’s alkaloidal fraction lacked narcotic properties, and was probably largely narcotine (also known as noscapine), perhaps with meconic acid, both abundant in opium. Armand Seguin read a paper to the Institute of France in 1804, but only published it in 1814 (9). He described the isolation of a principle, but did not report any animal or human experiments. The relationship between toxicity and therapy was an ancient concept. Walter Raleigh wrote, in 1614 (10), “The skillful and learned chemist could draw helpful medicines out of poison, as poison out of the most helpful herbs and plants.” Shakespeare refers to the same principle more poetically in

In other words, he gave about 32 milligrams of material, comparable to a 60-milligram average oral adult dose of a morphine salt (7).

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Henry IV, part 2: “[I]n poison there is physic.” However, Sertürner helped establish the relationship as an experimental principle, thereby stimulating an era of chemical and pharmacological progress. He explicitly recognized that an extract of opium would have a purity and reproducibility of effect not obtainable with raw opium. He generalized the principle that other “so-called poisonous plants” would contain extractable materials with potential therapeutic activities. Sertürner initiated the development of natural product chemistry, and he stimulated the evolution of synthetic and degradative chemistry for the structural elucidation of complex crystalline chemicals isolated from plants. Initially, the emphasis was on alkaloid isolation, because of the ease of acid extraction of alkaloid salts and the ease of purification by organic extraction of lipophilic free alkaloids from basified medium. Winterstein and Trier (11) write that alkaloid chemistry began in 1817. Hanzlik (12) comments, “The isolation of morphine was a comparatively humble achievement. It required no munificent grant, no extensive laboratory equipment, no highly organized institute or factory.” In view of its dream-inducing properties, Sertürner named his crystalline material “morphium,” derived from “Morpheus,” the Latin name that Ovid (43 BC - 17 AD) used for the god of dreams (Metamorphoses, Book XI). Morpheus was the son of Somnus, the god of sleep. Ovid derived the word from the Greek morphe, or form, because the god of dreams gives airy nothings their form and fashion (13): King Sleep was father of a thousand sons– indeed a tribe – and of them all, the one he chose was Morpheus, who had such skill in miming any human form at will. Despite the derivation, Morpheus is a Roman invention, and not Greek. (In Hesiod, dreams were the daughters, and not the sons, of Night.) It was Joseph Louis Gay-Lussac who introduced the form “morphine,” against the objections of Sertürner (14). The Oxford English Dictionary has the first citation in English in 1828: “morphine is the narcotic principle of opium.” Ryan J. Huxtable Department of Pharmacology College of Medicine University of Arizona Tucson, Arizona 85724-5050

Stephan K. W. Schwarz Centre for Anesthesia & Analgesia Dept. of Pharmacology & Therapeutics and Dept. of Anesthesia Faculty of Medicine The University of British Columbia Vancouver, B.C. Canada V6T 1Z3

Acknowledgment
We thank Marion Huxtable for help with translations from the German.

REFERENCES
1. Goodman, L. and Gilman, A. The Pharmacological Basis of Therapeutics. New York: The Macmillan Co., 1941, p. 186. 2. Goodman, L. and Gilman, A. The Pharmacological Basis of Therapeutics. New York: The Macmillan Co., 1958, p. 216. 3. Gilman, A.G., Goodman, L.S., Rall, T.W., and Murad, F. The Pharmacological Basis of Therapeutics. New York: MacMillan Publishing Co., 1985, p. 491. 4. Sertürner, F. [No title]. Journal der Pharmacie fuer Aerzte und Apotheker 13: 229-243, 1805. 5. Sertürner. Darstellung der reinen Mohnsäure (Opiumsäure) nebst einer Chemischen Untersuchung des Opiums mit vorzüglicher Hinsicht auf einen darin neu entdeckten Stoff und die dahin gehörigen Bemerkungen. Journal der Pharmacie fuer Aerzte und Apotheker 14: 47-93, 1806. 6. Sertuerner. Ueber das Morphium, eine neue salzfähige Grundlage, und die Mekonsäure, als Hauptbestandtheile des Opiums. Annalen der Physik 55: 56-89, 1817. 7. Hardman, J.G., Limbird, L.E., Molinoff, P.B., Ruddon, R.W., and Gilman, A.G. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw Hill, 1995, 8. Derosne, C.L. Mémoire sur l’opium. Ann.Chim. 45: 257-285, 1803. 9. Seguin, M.A. Premier memoire sur l’opium. Annales de Chimie 92: 225-245, 1814. 10. Raleigh, W. The History of the World I I Chap. 7, p71. London: 1614. 11. Winterstein, E. and Trier, G. Die Alkaloide. Berlin: Borntraeger Press, 1910. 12. Hanzlik, P.J. 125th Anniversary of the discovery of morphine by Sertürner. J. Am. Pharm. A. 18: 375-384, 1929. 13. Mandelbaum, A. The Metamorphoses of Ovid. New York: Harcourt Brace and Co., 1993. 14. Sertuerner, F.W. Ueber eins der fürchterlichsten Gifte der Pflanzenwelt, als ein Nachtrag zu seiner Abhandlung über die Mekonsäure und das Morphium; mit Bemerkungen, den aciden Extractivstoff des Opiums und seine Verbindungen betreffend. Annalen der Physik 57: 183-202, 1817.

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