COMMENTARY

The origins of chemical

Kim L Morrison & Gregory A Weiss

Chemical biology has historical roots that date back to the birth of and biology as distinct .

The origins of can be traced own experiments on , referred to as ‘airs’ to the enormous technological and scientific in the parlance of the time2. Priestley, perhaps advances of the nineteenth century, resulting most identified with the discovery of , in the field’s ascent in the twentieth century. also isolated at least ten other gases, includ- Examining the nineteenth-century origins ing . Using biology to advance of chemical biology serves at least two pur- chemistry, Priestley incubated mice with these poses. First, the history of provides a gases. The approach provided a primitive framework for teaching. Descriptions of clas- characterization method (upon exposure to a sic experiments and breakthroughs can equip compound, does a mouse live or die?) that has teachers and students with examples illustrat- since fallen into disfavor with synthetic chem- ing key concepts. Second, the historical roots ists. The experiments also inspired early ani- of chemical biology inform us that the field has mal-rights sentiments, including “The Mouse’s always identified exciting new ques- Petition,” a poem by Priestley’s friend Anna tions and challenges. Such a record promises Laetitia Aikin Barbauld (Box 1)3. Widespread a bright future for the field. condemnation of Priestley followed publi- Chemical Biology defines chemical cation of the poem, fueling discontent with biology as both the use of chemistry to advance his political leanings, which included a molecular understanding of biology and the sympathy for the American colonies. Thus, an harnessing of biology to advance chemistry1. angry mob torched the home of perhaps the

Despite the veneer of newness associated with first chemical . ©V&A Images/Victoria and Albert Museum (www.vam.ac.uk) the term, chemical biology has early, albeit Turning the tables on Priestley’s approach Figure 1 A cyanotype from British and Foreign

© 2005 Nature Publishing Group http://www.nature.com/naturechemicalbiology modest, beginnings, extending back at least to chemical biology by using chemistry to Flowering and by Anna Atkins (circa two centuries to the masterworks considered advance biology, Sir Humphrey Davy’s experi- 1854). With characteristic artistry, Atkins captured the foundations of chemistry and biology. This ments with newly isolated, unfamiliar gases two stages of feathery dandelion blossoms. brief article presents a few intriguing histories omitted the mouse entirely. In what must be that define the beginnings of chemical biol- considered an act of either lunacy or egotism, ogy. Given its limited scope, however, many Davy (1778–1829) carried out his experiments continues to the present day, reaching a high examples of the hard work, heartbreak, inno- on himself. Not surprisingly, his experiments point with the 1998 won by Robert vation and patience integral to the field have with monoxide almost proved fatal. In Furchgott, Louis Ignarro and for had to be omitted. one experiment, Davy inhaled four quarts of demonstrating the key roles played by nitric The history of nitrous oxide, discovered nitrous oxide isolated in a silk bag. The pleas- oxide in signaling. in 1772 by Joseph Priestley, provides a classic ant intoxicating effect of the inspired Davy Establishing the importance of synthetic example of the yin and the yang of chemical to name it laughing gas. A popular in chemistry to chemical biology, Friedrich biology. Inspired by Benjamin Franklin’s work the late eighteenth century (and to a lesser Wöhler’s fortuitous accident in 1828 led the on , the radical theologian Joseph extent today), nitrous oxide is believed to have way to the formulation of a chemical basis for Priestley (1733–1804) began to perform his influenced many of the celebrated works of . During an attempt to synthesize ammo- one pleasure seeker, the author Samuel Taylor nium cyanate, Wöhler (1800–1882) heated Coleridge4. Although Davy had noted the a solution of silver cyanate and Gregory A. Weiss is in the Departments of possible advantages of using nitrous oxide chloride. Separately, he also heated cya- Chemistry, and , in surgical procedures, medical uses for the nate and aqueous . In both cases, he and Kim L. Morrison is in the Department of gas remained unexplored until experiments obtained not the expected , but urea History at the University of California, Irvine, by the American dentist Horace Wells in 1844 (Scheme 1)6,7. Wöhler’s synthesis showed that California 92697-2025, USA. (ref. 5). Application of the chemistry of nitro- inorganic starting materials could be used to e-mail: [email protected] gen oxides to advance biology and synthesize substances previously associated

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Expected 12 ∆ process for an intensely blue, monochromatic von Bismarck . Equally undaunted by hostility + – + – 9 AgOCN + NH4 Cl NH4 OCN + AgCl color photography . The cyanotype process from his scientific peers, Virchow vehemently relies on -sensitive paper doped with opposed germ theory, arguing instead that the Obtained O salts to produce negative images where causes of disease lay within the cells themselves. + – ∆ the imaged sample blocks exposure to light. In Discouraged and exasperated, Virchow eventu- AgOCN + NH4 Cl H2N NH2 her own time, Atkins established a repu- ally abandoned both politics and science for tation as a collector, botanist and scientific the seemingly more attainable goal of finding Scheme 1 Wöhler’s synthesis of urea. Yielding illustrator. Elected a member of the Botanical Homer’s Troy. Nonetheless, Virchow’s studies, a chemical previously isolated only from man or dog, the synthesis of urea represented a Society of London in 1839, a remarkable particularly on leukemia, resulted in an explosion 13 landmark achievement in and accomplishment for a woman in the mid- of interest in cell and . chemical biology. nineteenth century, Atkins applied Herschel’s In 1856, as the Austrian monk cyanotype process to document delicate began his studies of the genetic basis for hered- botanical specimens (Fig. 1). Atkins published ity, an 18-year-old British , William her images in the first photographically illus- Perkin (1838–1907), worked diligently through only with living . In other words, trated book (either scientific or nonscientific), the night in his seeking a treatment requires no ‘living’ or ‘vital British : Cyanotype Impressions (1843)10. for malaria. While attempting to synthesize the force’ to make biologically active compounds. Atkins’s photograms render a transparency to alkaloid quinine, Perkin serendipitously dis- Remarkably, some belief in vitalism still per- the stained objects, making the intricate details covered the first dye, which he called sists within current popular culture. For exam- of her specimens remarkably clear. Art galler- mauveine for its brilliant violet color (Fig. 2a)14. ple, the public continues to pay a premium for ies, such as the Getty Museum in Los Angeles, Whereas the dazzle of -produced and other supplements isolated from still display her work11. transformed the fashion houses of Europe, the natural sources8. Synthesis, of course, continues Synthetic chemistry in the nineteenth century, 1856 discovery of mauve had far-reaching to play a key role in chemical biology, includ- especially the synthesis of aniline dyes, is inextri- implications for biological research, sparking ing the present frontiers of diversity-oriented cably linked to early . As improvements the development of modern medicine15. For synthesis and chemical . to and chemical dyes uncovered fine example, realized the pharmaceu- Another prevalent theme in contemporary within the cell, (1821– tical potential of coal tar derivatives and sug- chemical biology, cellular imaging, was revo- 1902) published Die Cellularpathologie in 1858. gested such treatments could provide ‘magic lutionized by chemical approaches first devel- This text established two key principles. First, all bullets’ for precise targeting of disease. oped during the nineteenth century. One early cells descend from other living cells, and, second, The cigar-smoking Ehrlich (1854–1915) innovator, Anna Atkins (1799–1871), learned cellular changes can result in disease. Virchow’s devoted his early life’s work to applying a science firsthand from her father, a prominent theory of cellular transformed scien- chemical approach to the visualization of living botanist, and his circle of friends, including tific understanding of biology and revolution- cells. Ehrlich experimented with the newly Sir Humphry Davy, Sir John Herschel and ized the field of medicine. Virchow also bravely discovered aniline dyes derived from coal tar William Henry Fox Talbot (the ‘father of pho- served in the German Reichstag in opposition and found that some dyes could differentially tography’). Herschel invented the cyanotype to the Chancellor of “blood and iron,” Otto stain specific cells and tissues. He correctly surmised that this difference resulted from a of the dyes with specific substances within the cells16. For example,

© 2005 Nature Publishing Group http://www.nature.com/naturechemicalbiology the predominant basicity of dyes capable of cell nuclei led Ehrlich to term the nucleus “basophilic.” Applying the aniline blue dyes for diagnostics, Ehrlich identified a tiny rod-shaped bacterium as the culprit responsible for tuberculosis. Ehrlich’s insight into the intracellular reduction of various synthetic dyes led to amazing leaps in medicine, pioneering the earliest form of and drug . For example, Ehrlich proposed the development of magic bullets or toxins capable of targeting specific pathogens. In the first example of a magic bullet, Ehrlich discovered a chemical, Salvarsan or Ehrlich’s 606th (named in tribute to the 605 preceding failed compounds; Fig. 2b), to treat syphilis. Salvarsan became a blockbuster in its time and replaced the earlier treatment of mercury, which caused blackened teeth and 17 Image copyright of Wellcome , London Library, Image copyright of Wellcome baldness . The success of Salvarsan paved Sir Humphry Davy (right, with bellows) presents his newly isolated airs to the Royal Institution, the way for new , ultimately fulfilling London. Caricature by James Gillray (1802). Image copyright and used with permission of the Perkin’s initial experimental goal of finding Wellcome Library, London. a treatment for malaria.

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a b NH2 BOX 1 EXCERPT FROM R HO THE MOUSE’S PETITION H3C N CH3 OH! hear a pensive captive’s prayer, For liberty that sighs; As As And never let thine heart be shut H2N N N H Against the prisoner’s cries. For here forlorn and sad I sit, NH2 Within the wiry grate; And tremble at th’ approaching morn, OH Which brings impending fate. If e’er thy breast with freedom glow’d, Figure 2 Structures. (a) Mauveine (R = mixture of CH and H). (b) Salvarsan. Although it was 3 And spurn’d a tyrant’s chain, structurally characterized only recently13, mauveine sparked a nineteenth-century revolution in chemistry and chemical biology. Discovered by Paul Ehrlich, Salvarsan demonstrated the Let not thy strong oppressive force of the magic bullet approach to treating disease. A free-born mouse detain. —Anna Laetitia Aikin Barbauld

Contemporaneously, Swiss exciting results was delayed by the editor of the Aikin, A.L. The mouse’s petition in Poems (Joseph Johnson, London, 1773). Reprinted online in Romantic Circles (Vargo, L. & Muri, A., Friedrich Miescher (1844–1895) took the first first biochemistry journal, Ernst Felix Hoppe- eds.). Accessed 15 November 2005 (http://www.rc.umd.edu/editions/ concrete steps toward the eventual discovery of Seyler, who insisted on repeating and verify- contemps/barbauld/poems1773/mouses_petition.html/). the double helical structure of DNA by James ing the experimental results. Although many Watson and . Interested in the in the field disputed his discovery, Miescher substructure of the cell, Miescher focused on continued to use chemical methods to unravel nent early chemical staked out con- the identification of in the nucleus. the mysteries of the cell. Miescher’s student, troversial, public positions in the political Miescher made the practical, though slightly Richard Altmann, coined the term “nucleic debates of the day. Though their views were unpleasant, decision to use human leukocytes ” to more accurately describe nuclein in quite unpopular at the time, such courage readily available in copious quantities from the 1889 (ref. 19). illustrates the role leading-edge can pus-soaked bandages of a nearby surgical clinic. The explosion of research at the chemis- play in the national discourse. For example, After working out conditions to separate intact try-biology interface continues to the present many contemporary chemical biology experi- cells from the bandages, Miescher next devised day. The field remains driven by emerging ments make use of molecular evolu- a procedure to isolate their nuclei, through , such as microarrays, molecular tion, and could offer a useful counterpoint to treatment with warm to remove display libraries, single- techniques the ongoing debates over teaching . of the membrane, followed by proteo- and combinatorial . Many current Second, our present considerably advanced lytic digestion of the with pepsin and chemical biologists emphasize the use of small state of knowledge in chemical biology did of intact nuclei. Using chemistry to control cellular processes20. not emerge from a smooth arc of progress. to advance biology, Miescher analyzed the con- This approach to chemical biology would be In fact, serendipity played a key role in sev- tents of his purified nuclei with the chemical familiar to its earliest practitioners, such as the eral key advances cited here. Third and most

© 2005 Nature Publishing Group http://www.nature.com/naturechemicalbiology tools of the day—elemental analysis, digestion magic bullet proponent, Paul Ehrlich. Similarly, importantly, the historical record and current by various proteases and in various using chemistry to enhance imaging has been studies show the effectiveness of the chemical solutions. In 1869, he recorded the following in a longstanding interest of chemical biologists biology approach for advancing both chem- a lab notebook (translated from German): from Anna Atkins onward. Of course, much istry and biology. has changed since the nineteenth century, from In the experiment with the weakly alka- the analytical tools to the addition of powerful line fluids, I obtained, by neutralization molecular biology techniques. of the solutions, precipitates which were In summary, although the term would insoluble in , , very dilute not be coined for at least a century, the roots hydrochloric acid, or chloride solu- of our field can be found in both biological tions; consequently, they could not belong and chemical experiments that today would to any of the known albuminoid substances. clearly be classified under the heading of Where did this substance come from?18 chemical biology. Examining history uncovers other interesting . First, several promi- Miescher called this substance “nuclein” and found that its elemental composition included not only the usual assortment of carbon, hydro- Paul Ehrlich (circa 1913) in his laboratory. gen, oxygen and of known organic Winner of the Nobel Prize (in 1908, which chemicals but also, surprisingly, phosphorus. he shared with Élie Metchnikoff), Ehrlich contributed groundbreaking discoveries in several Miescher’s use of chemistry to initiate the faint areas, including cell imaging with aniline dyes, beginnings of molecular biology did not cause development of the magic bullet concept and the sensation that one might expect for such a antigen-mediated immune response. Image © key advance. Indeed, publication of Miescher’s Wellcome Library, London. Used with permission. London Library, Image copyright of Wellcome

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ACKNOWLEDGMENTS (1996). 1, 5–7 (1994). We thank G. Fenteany, R. Martin and other readers 9. Schaaf, L. Out of the Shadows: Herschel, Talbot and the 14. Garfield, S. Mauve: How One Man Invented a Color that for their helpful comments. Invention of Photography (Yale Univ. Press, New Haven, Changed the World (W.W. Norton, New York, 2000). 1992). 15. Ehrlich, P. Arch. Mikr. Anat. 13, 263–277 (1877). 1. Anonymous. Nat. Chem. Biol. 1, 3 (2005). 10. Atkins, A.A. Photographs of British Algae: Cyanotype 16. Schiller, F. Clio Med. 5, 145–155 (1970). 2. Priestley, J. Experiments and Observations on Different Impressions Vols. 1–3 (privately published, Halstead 17. Miescher, F. Die Histochemischen und Physiologischen Kinds of Air (Johnson Press, London, 1774). Place, Sevenoaks, 1843–1853). Arbeiten (Vogel, Leipzig, 1897). 3. Ready, K.J. Eighteenth-Cent. Life 28, 92–114 (2004). 11. Gribbin, J. The Scientists: A Told 18. Miescher, F. Hoppe-Seyler’s Med. Chem. Unt. 13, 441– 4. Hoover, S.R. B. Res. Humanities 81, 9–27 (1978). Through the of its Greatest Inventors (Random 460 (1871). 5. Wright, A.J. J. Clin. Anesth. 7, 347–355 (1995). House, New York, 2004). 19. Fruton, J.S. Proteins, , : The Interplay of 6. Wöhler, F. Poggendorff’s Ann. 12, 253–256 (1828). 12. Toulmin, S. & Goodfield, J. The Architecture of Chemistry and Biology (Yale Univ. Press, New Haven, 7. Wöhler, F. Ann. Chim. Phys. 37, 330–333 (1828). (Univ. Chicago Press, Chicago, 1962). 1999). 8. Cohen, P.S. & Cohen, S.M. J. Chem. Ed. 73, 883–886 13. Meth-Cohn, O. & Smith, M. J. Chem. Soc. Perkin Trans. 20. Schreiber, S.L. Nat. Chem. Biol. 1, 64–66 (2005). © 2005 Nature Publishing Group http://www.nature.com/naturechemicalbiology

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