ORIGINAL ARTICLES

Faculty of Pharmacy and CEIS20, University of Coimbra, Coimbra, Portugal

The influence of German science on and quinine research in Portugal in the second half of the 19th century

M.G. SEMEDO*, A.L. PEREIRA, J.R. PITA

Received March 23, 2021, accepted April 30, 2021 *Corresponding author: M. G. Semedo, Faculdade de Farmácia da Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal [email protected] Pharmazie 76: 396-402 (2021) doi: 10.1691/ph.2021.1050

This paper examines the contribution of three Portuguese scientists to Cinchona cultivation in the former Portu- guese colonies in the second half of the 19th century, while discussing the importance of their studies in Germany to their professional lives. Portuguese pharmaceutical, medical, and botanical literature from the 19th and 20th century was reviewed, as well as books and articles regarding the history of pharmacy and medicine in Portugal. Cinchona bark, source of the antimalarial alkaloid quinine, is obtained from a South American , and was an important commodity in the 19th century. Many European nations (including Portugal) tried to acclimatize and cultivate Cinchona in their colonies. Pharmacist Joaquim dos Santos e Silva (1842–1906) performed chemical analysis of Cinchona bark samples from the Portuguese colonies in Africa. Forester Bernardino Barros Gomes (1839–1910) wrote a book with practical instructions for Cinchona cultivation and chronicled the history of Cinchona plantations in the British and Dutch colonies. In that work he also encouraged private planters to cultivate Cinchona. Forester Adolpho Frederico Möller (1842–1920), as inspector of the Botanical Garden of Coimbra, managed Cinchona plants’ cultivation in the garden’s nurseries, which were later sent to the colonies, and answered queries from Cinchona planters. Silva’s chemistry studies in Germany were crucial to his career and the work of the three scientists was influenced and guided by their knowledge of German science and scientific culture.

1. Introduction British with the support of the Royal Botanic Gardens at Kew and The plant genus Cinchona includes about 23 (Andersson other botanic gardens in the British colonies (Brockway 2002). 1998), native to South America (Andrés Turrión 2005). Cinchona Cinchona planters in British India and Ceylon became the main bark (also known as quina) has antimalarial activity. The major producers worldwide until the early 1890s (Van der Hoogte and Cinchona alkaloids are quinine, cinchonine, quinidine and Pieters 2015). cinchonidine (Kacprzak 2013). Quinine is still used for malaria In the 1860s and 70s the German pharmaceutical industry treatment (Moore 2019). conducted studies on Cinchona bark and quinine, seeking to opti- In the early 19th century, the use of Cinchona bark to treat inter- mise the extraction of quinine (Van der Hoogte and Pieters 2014). mittent fever was well established (Gachelin et al. 2017). Medical In the 1870s, the Dutch improved Cinchona cultivation. Through historiography has tied up intermittent fevers with malaria (Stanley chemical research and the selection and protection of Cinchona et al. 1991). Due to the therapeutic value of the Cinchona bark, varieties richest in quinine, the Dutch managed to obtain stan- several scientists sought to identify the substances that conferred dardised, high-quality Cinchona bark (Van der Hoogte and Pieters on it such febrifuge properties. Subsequently, cinchonine was 2015). With the selection of high-yielding Cinchona specimens, isolated in 1810 (Gomes 1812; Silva 2015) and quinine in 1820 Cinchona cultivation became more appealing to Dutch private (Pelletier and Caventou 1820). In 1833, quinidine was isolated entrepreneurship, which fostered increase in production in the (Henri and Delondre 1833, 1834) and in 1847 it was cinchoni- Dutch East Indies. Dutch production was partly sold to the Euro- dine’s turn (Winckler 1847). In the same year of its isolation, the pean pharmaceutical industry, mainly to German companies (Van effect of quinine on intermittent fevers was tested (Double 1820). der Hoogte and Pieters 2015). Growing supply brought the price of Quinine began to be produced in countries like France, the United Cinchona bark down, and the production of Cinchona in the British Kingdom and Germany (Webb Junior 2009). colonies in India and Ceylon was abandoned (Van der Hoogte and Gradually there was also the idea that Cinchona were Pieters 2015). The Dutch continued to produce Cinchona and by becoming extinct due to inappropriate harvesting methods and the 1920s they had a monopoly on Cinchona bark and quinine’s overexploitation in the Andes. Therefore, European intervention trade and production (Van der Hoogte and Pieters 2015). was intended to prevent the extinction (Brockway 2002). Several Like other countries, Portugal also sought to grow Cinchona on scientists called for the cultivation of Cinchona outside its place its colonies, namely on the island of São Tomé (Fig. 1), and in of origin (Costa 1944). The Dutch and British governments sent Cabo Verde, Timor, and Angola (Costa 1944). The director of scientists to South America to gather Cinchona seeds and plants the Botanical Garden of Coimbra, who also taught botany at the (Brockway 2002; Van der Hoogte and Pieters 2014). Faculty of Philosophy of the University of Coimbra, Professor The Dutch were the first to successfully transfer Cinchona seeds Júlio Henriques (1838–1928), was one of the biggest supporters and plants to their colonies in the East Indies in the early 1850s of growing Cinchona plants in the Portuguese territories overseas (Van der Hoogte and Pieters 2014). The British also managed to (Silva Machado 1882; Costa 1944). He ordered seeds from other cultivate Cinchona in their Asian colonies, especially in India botanical gardens, i.e., Buitenzorg (in Java) and had Cinchona and Ceylon (Brockway 2002). Cinchona was farmed by the plants grown in the nursery of the botanical garden. Furthermore, 396 Pharmazie 76 (2021) ORIGINAL ARTICLES

2.1. Bernardino Barros Gomes 2.1.1. Bernardino Barros Gomes (1839–1910): biograph- ical outline Bernardino Barros Gomes was born on September 30th, 1839, in the Portuguese city of Lisbon. His grandfather was the physician, chemist, and botanist Bernardino António Gomes (1768–1823), who isolated cinchonine in 1810. His father, Bernardino António Gomes (1806–1877), was a physician also linked to the pharma- ceutical field. Barros Gomes’ father was the author of an important publication in Portugal, Elements of general Pharmacology or the general principles of medicine and therapy (Elementos da Farmacologia geral ou princípios gerais de matéria médica e terapêutica, 1863). The father of Bernardino Barros Gomes was also chairman of the committee which drafted the third official Portuguese pharmacopoeia in 1876. At the University of Coimbra, Barros Gomes attended the Faculty of Mathematics for four years, and the Faculty of Philosophy for five years. In 1860, Barros Gomes was trained in Philosophy at the University of Coimbra (Guimarães 2006). Gomes then went on to study in Germany. In 1861 he enrolled as a foreign student at the Royal Saxon Academy of Forestry (Königlich-Sächsische Forstakademie) in Tharandt, Saxony (Guimarães 2006). In 1861 and 1862, he was a foreign student at the Königlich-Säch- Fig. 1: Bag with Cinchona calisaya from São Tomé island. First half of the 20th sische Forstakademie (Devy-Vareta 1998; Pereda 2018), where century. Collection of the Faculty of Pharmacy of the University of Coimbra he studied agronomy and forestry (Garcia 1988). The diploma (with permission). of the studies he attended and completed dates from March 31st, 1862 (Silva 1867; Guimarães 2006). In the 19th century, another Portuguese forester was trained at the same school of forestry (Pereda 2018). Before returning to Portugal, he went to a scientific expedition in the north of Germany, aimed at Henriques had Cinchona seeds and live plants sent to the Portu- learning more about “matters concerning the exploration and guese colonies (Costa 1944). Júlio Henriques and others (Machado plantation of forests” (Gomes 1865). The publication Archivo 1882; Hopffer 1876) also called on the government to actively Rural reports part of the information gathered, namely on “the support Cinchona cultivation in the colonies, namely by setting German national forests planning and management system” up state-owned nurseries (Henriques 1876; Machado 1882). The (Gomes 1865; Guimarães 2006). He met his future wife in Portuguese government encouraged the development of literature 1 Tharandt, Elisa von Wilcke, the daughter of Otto Moritz Baron on Cinchona farming (Silva 1867; Machado 1882) and recom- von Wilcke. In 1866, they got married in Dresden (Guimarães mended that the Governors in the colonies promote cultivation 2006). thereof (Costa 1944). However, despite such dispersed initiatives, When he returned to Portugal in 1863, Gomes joined the Agricul- apparently the Portuguese government made no concerted effort tural Department of the Ministry of Public Works (1863) and later to foster Cinchona cultivation. Unlike the Dutch in Java, no a Decree of 24 October 1864 made him junior official engineer. experimental stations were set up in the Portuguese colonies, nor The return to Portugal of Barros Gomes marked the adoption of specific laboratories for conducting chemical analyses systemati- parameters of the “international forest community” by the Portu- cally to samples of Cinchona bark from the colonies. Nonetheless, guese forestry sector, and large-scale forestry works were carried the government did engage in some initiatives to study Cinchona out, “suitably planned and with well-established targets” (Pereda bark’s chemical and medicinal properties in the beginning of the 2018). 19th century that were important for isolating cinchonine (Castilho His scientific production includes a book on Cinchona, Cultivation 1814a; Castilho 1814b; Costa 1944). of the plants that produce Cinchona bark (Cultura das Plantas The Cinchona cultivation attempts by the Portuguese were most que dão a Quina, 1864), publications on forestry, e.g., the papers fruitful in the island of São Tomé. But the São Tomé Cinchona stemming from the study he carried out in Germany (Pereda 2018) plantations were made up of plants with low quinine content, and and geography, such as Elementary maps of Portugal for use in therefore unable to compete with the Dutch plantations of high- quality bark (Cabral et al. 2015). schools (Cartas elementares de Portugal para uso das escolas, This paper examines the contribution of three Portuguese scientists 1878). He also wrote forestry reports stemming from his work as a to Cinchona cultivation in the Portuguese colonies in the second Portuguese civil servant. half of the 19th century. It also discusses the impact of the studies Gomes was appointed manager of the Northern Division of the they carried out in Germany on their professional lives. Royal General Administration of Forests by Decree of 22 June They were the pharmacist Joaquim dos Santos e Silva (1842– 1872 (Guimarães 2006). In 1874 he was appointed director of 1906), and the foresters Adolpho Frederico Möller (1842–1920) the Southern Division of the Royal General Administration of and Bernardino Barros Gomes (1839–1910). Forests (Guimarães 2006). In 1879 he began working at the Central Division of the Royal General Administration of Forests (Guimarães 2006). He studied and managed the Pine Forest of 2. Investigations, results and discussion Leiria and drew its full plan (Guimarães 2006). Furthermore, An historical review of pharmaceutical and medical literature he became corresponding member of the Royal Academy of from the second half of the 19th century and the first half of the Sciences of Lisbon (Academia Real das Ciências de Lisboa) 20th century, namely Portuguese medical, pharmaceutical, and (Silva 1867). botanical books and academic journals (both in physical and When his wife died, he submitted his resignation from office at the digital libraries). Several articles published by Joaquim dos Santos Central Division of the Royal General Administration of Forests e Silva and Adolpho Möller regarding Cinchona and/or quinine (accepted in 1883) and became a priest in 1888 (Garcia 1988; were located and reviewed. A book on Cinchona cultivation by Ferreira 2007; Guimarães 2006). He was murdered in 1910 by Bernardino Barros Gomes was also analyzed. revolutionary Republicans (Guimarães 2006; Ferreira 2007). Pharmazie 76 (2021) 397 ORIGINAL ARTICLES

2.1.2. Bernardino Barros Gomes’s research on Cinchona data on Cinchona cultivation in the British and Dutch colonies. In 1864, Bernardino Barros Gomes published a book called Afterwards, he listed the measures the Portuguese government Cultivation of the plants that produce Cinchona bark (Cultura had taken to grow Cinchona. As the Austrian explorer and botanist das plantas que dão a Quina) (Fig. 2). Later the book was also Dr. Friedrich Martin Josef Welwitsch (1806–1872) had suggested, published in academic journals: in tome 29 of the medical journal Navy Minister José da Silva Mendes Leal (1820–1886) instructed Jornal da Sociedade das Sciencias medicas in 1865 (Silva 1867), that seeds of the plants be collected, and 30,000 seeds of Cinchona and in the pharmaceutical journal Jornal da Sociedade Pharma- pahudiana from Java were received. However, Gomes warns that ceutica Lusitana, in 1865 and 1866, in the form of 14 papers. it was not a suitable species, because its bark had a total alkaloid The book was divided into four chapters, containing an appendix content of “no more that 0.4%” (Gomes 1864 p. 19) and there- and five prints (Gomes 1864). It was commissioned by the Portu- fore little medicinal value. Even so “important resources” of the guese government, who sought to encourage widespread Cinchona Portuguese people were expected to be channelled towards the cultivation in the Portuguese territories, namely in the Portuguese development of the “Government’s enlightened initiative on this colonies in Africa and Asia (Silva 1867). matter” (Gomes 1864 p. 76). Gomes found that to ensure successful Cinchona crops a large variety of seeds had to be acquired (“a good collection of all varieties farmed by the English and Dutch”), thus ensuring that some of the species would adjust to the colonies’ climates (Gomes 1864 p. 18). Then, the best places for sowing the seeds had to be selected. Consequently, botanical and meteorological studies on the Portuguese colonies’ climates were needed to compare them with the climate in the region where the Cinchona is indigenous to (Gomes 1864). In his book, Gomes hoped to “raise awareness of those who on our islands and colonies are interested in growing cinchona to the most important aspects that must be considered when choosing the places to farm” (Gomes 1864 p. 85). He provided a bibliography on Cinchona cultivation, described directly how to grow Cinchona plants and summarised known information about the meteoro- logical and botanical features of the Portuguese colonies and the islands of Azores and Madeira. He warned, however, that more meteorological and botanical data had to be gathered. The author hoped that regions belonging at the time to the Portuguese territory would “welcome” the Cinchona trees, the “precious febrifuge trees” (Gomes 1864 p. 111) and identified places where Cinchona could be farmed. Such were the islands of Azores and Madeira, Cabo Verde, São Tomé, Angola, Timor, and the Portuguese terri- tory in India. According to Gomes, part of the bibliography was available in Portugal, but it was necessary to acquire and translate the best books on Cinchona cultivation to inform potential farmers. In addition, he says that “short but good practical instructions should be added about the extreme weather to be feared for the new plants, the most suitable exposures and altitudes for each species in each of the colonial climates, where we can try growing them” (Gomes 1864 p. 20). Gomes encouraged further potential stakeholders to grow the Cinchona , alluding to the “civilising mission of European settlers and conquerors” to introduce a plant that had useful and recognised properties (Gomes 1864 p. 110). According to the author, the successful introduction of the Cinchona on Portuguese territory would originate a valuable industry and would also provide “efficient support to European colonisation” (Gomes 1864 p. 85). Gomes said that “The way forward was the path drawn and opened by foreign industry. We have all the seeds and seedlings we need in the nurseries in England, British India and Java, now that they are widely disseminated. The experience of Dutch and English farmers will guide us in our first steps” (Gomes 1864 p. 110). Gomes felt that the Botanical Garden of Coimbra should play a role similar to that Fig. 2: Frontispiece of Cultivation of the plants that produce Cinchona bark (Cultura das plantas que dão a quina) published in 1864 by Bernardino Barros Gomes of the Kew Botanic Gardens in Great Britain and the Dutch gardens (1839–1910). of the Universities of Leiden and Utrecht. He also suggested that the nursery that had been recently built in the Botanical Garden of Coimbra should be used to grow Cinchona plants that would be introduced in the African colonies (Gomes 1864). Gomes wrote first about the therapeutic value of quinine and high- In the book’s appendix, he listed the botanical characteristics of the lighted that the trees and from which Cinchona bark (the Cinchona genus and the “cultivated species or varieties” (Gomes raw material of quinine) was extracted were still mostly restricted 1864 p. 114). to their native habitat. He specified the most important Cinchona Gomes clearly contributed to stimulating Cinchona cultivation by species and their native habitat and highlighted the plants that are highlighting in his work the therapeutic importance of the plant generally found near them (Gomes 1864). and its role as adjuvant of European colonization. In addition, he The author underscored further that Cinchona cultivation by suggested using the nurseries at the Botanical Garden of Coimbra the British and the Dutch were the “two biggest examples that to grow Cinchona plants for the Portuguese colonies, which did should be followed” (Gomes 1864 p. 17) and provided historical happen (Machado 1882). 398 Pharmazie 76 (2021) ORIGINAL ARTICLES

2.2. Adolpho Frederico Möller 1885). Möller gathered plant and animal species there (Henriques 1924). Furthermore, he performed herborization work in different 2.2.1. Adolpho Frederico Möller (1842–1920): brief places in Portugal (Henriques 1924). These botanical expeditions biography resulted in the discovery of new plants, some named in honour of Adolpho Frederico Möller (Fig. 3) was born in Lisbon in 1842. Möller (Henriques 1924). His parents, Henrique Möller and Henriqueta Sophia Lindenberg, He promoted the development of forest tree nurseries (namely by were of German descent (Junior 1885). He attended primary and the Mondego river) and encouraged the afforestation of Portugal. secondary school at the Luso-British and German Schools (Junior The seeds for the nurseries in the Mondego area were mostly from 1885; Henriques 1924). In 1857, he obtained a scholarship to Haage & Schmidt, a German company from Erfurt (Pereda 2018). study in Germany (Pereda 2018) He studied Practical Forestry He helped to develop herbariums, such as Schultz’s “Herbarium in Germany for three years, from 1857 to 1860 and returned to Normale” or the “Medical Herbarium of the Office of Materia Portugal in 1860 (Henriques 1924). Medica of the University of Coimbra” (Junior 1885). Concerning his written production, he published papers in Portuguese and German scientific journals (e.g., Berichte der Deutschen Pharma- ceutischen Gesellschaft and Der Tropenpflanzer) and plant cata- logues (Pereda 2018). His papers addressed all kinds of subjects, such as forestry, horticulture, and medical and pharmaceutical botany (Junior 1885). Möller also helped with the phenological research conducted by the Director of the Botanical Garden of Gießen, Doctor Heinrich Karl Hermann Hoffmann (1819–1891), by keeping phenological records of the plants found in the Botanical Garden of Coimbra (Henriques 1924). He worked as an Inspector of the Botanical Garden until 1914. Möller died in Lisbon in 1920 (Henriques 1924).

2.2.2. Adolpho Frederico Möller’s research on Cinchona In his work as inspector of the Botanical Garden of Coimbra (between 1874 and 1914), Möller contributed to the acclimatization of the Cinchona in the Portuguese colonies by managing the culti- vation thereof in the garden’s nurseries and assisting the director of the Botanical Garden of Coimbra, Júlio Henriques (Machado 1882; Henriques 1924). The plants grown in the Botanical Garden were then sent to the colonies. Möller also published several papers on the Cinchona plants (Möller 1877, 1878, 1885, 1887). A paper from 1877 provided information on different Cinchona species acclimatised by the Zoological and Acclimatisation Society of Victoria (in Australia). It included data on the natural habitat of the Cinchona species that were planted by the society, as well as their colour, height, and alkaloid content. He then discussed the most suitable locations for growing Cinchona, the ideal temperature, the appropriate means of propagating the plants, how to increase the alkaloid content, when to start harvesting the bark, and indicated the price of bark in Europe. He concluded by saying that the colony of Australia had in 1869 about 3 million Cinchona trees from different species planted in the Darjeeling district (Möller 1877). In another paper published in 1878, Möller mentioned a visit from Joaquim Dias Quintas (correspondent in a company called Quintas & Irmãos that owned land on the island of São Tomé), who sought information about the cultivation of Cinchona (Möller 1878). The company intended to replace the coffee plantations with Cinchona plantations, due to low price of coffee on the market. Quintas asked the Chemistry Laboratory of the University of Coimbra Fig. 3: Adolpho Frederico Möller (1842–1920). Available at https://www.uc.pt/her- (Laboratorio Chimico da Universidade de Coimbra) to chemically bario_digital/history/Moller analyse a Cinchona bark sample from a plant that had grown in São Tomé. This plant had been sent to that island by the Botanical Garden of Coimbra. The company also wished to know the price of In Portugal, he worked at the Royal General Administration of bark by the kilogram and whether the Botanical Garden or even the Forests, the National Administration of the Machada and Vale government could deliver “some thousands of Cinchona plants” do Zebro Pine Forests, and the Coimbra Directorate for Public (Möller 1878). Möller advised Mr. Quintas to buy Bernardino Works (Junior 1885; Henriques 1924). He was also Manager of Barros Gomes’s book Cultivation of the plants that produce the Forest Department of the committee in charge of managing Cinchona bark (Cultura das plantas que dão a Quina, 1864) and the works in the Mondego area (Portuguese river that crosses the send it to the island of São Tomé and explained to him how to prop- city of Coimbra) (Junior 1885), and was part of the auxiliary civil agate Cinchona plants from cuttings. Since they did not have then engineering body. He began working at the Botanical Garden of “new Cinchona plants to ship”, they promised to send Cinchona Coimbra in 1874, as Inspector of the Botanical Garden (Henriques seeds as soon as the managers of the Botanical Garden received 1924), where he helped to promote agriculture in the Portuguese them (from Australia or Java). Möller added that in the Jornal de colonies, namely the cultivation of Cinchona. Horticultura Prática it had often been suggested that the Govern- In 1885, the Ministry of the Navy and Territories Overseas ment should seriously consider growing Cinchona, due to the high appointed him to a scientific expedition to São Tomé e Príncipe economic benefit. He highlighted further the great deal of effort (at the time a Portuguese colony) to study the native flora (Junior that the British and the Dutch put into acclimatising Cinchona in Pharmazie 76 (2021) 399 ORIGINAL ARTICLES their colonies. Möller also mentioned that the Botanical Garden of Coimbra had sent plants and seeds to some Portuguese colonies and that Júlio Henriques had played an important part in that and had published the results of Cinchona cultivation in the colonies. Möller stated that despite the good results of the quinine content of the samples from the colonies analysed by Joaquim dos Santos e Silva and the Botanical Garden’s endeavours, “we are not aware that our governments have done anything to propagate the culture of these plants”. According to Möller, Vasco Guedes Carvalho e Menezes (1824 –1905), during his time as Governor of Cabo Verde “had aspired at growing this plant, and created prizes for the farmers”, but he remained in office for only a short while and thus did not have the chance to develop these ideas. He concluded his paper by wishing that the then Navy Minister address the subject of Cinchona (Möller 1878). In another paper from 1885, written during a scientific expedi- tion to the island of São Tomé, Möller included various kinds of information on Cinchona cultivation in São Tomé, clarifying that at the time the island grew mostly coffee, cocoa, and Cinchona. According to Möller, “Here today there is the craze of cultivating Cinchona for those who have suitable land”, suggesting that farmers had turned to Cinchona cultivation with enthusiasm. He also speci- fied several farms that had Cinchona plantations. He alluded to the lack of the appropriate criteria for growing Cinchona; he said that some landowners did not value the quality of the Cinchona bark, but rather the amount, so they cultivated Cinchona succirubra, the species that grew the most and the fastest there. He stated that no Cinchona plants should be harvested without prior analysis of the bark “of individual species with the same age” to determine which species should be cultivated (Möller 1885). Another paper written in 1887 was about the information disclosed in the publication Gardener’s Chronicle, on the growth of Cinchona trees at low altitude that still produced bark with 6% alkaloids. According to Möller this suggested that “the production of these precious plants, for commercial purposes, was more valuable than initially assumed”. In the paper he also mentioned being in touch with Baron Sir Ferdinand Jacob Heinrich von Fig. 4: Joaquim dos Santos e Silva (1842-1906) (Source: Notícias Farmacêuticas 4, 1937-1938). Müller (1825–1896), a German botanist who worked in Australia. He had been the Director of the Botanical Garden of Melbourne and who “has extensively studied the cultivation of Cinchona plants in Australia”. He then went on to highlighting several of sent him to Germany to pursue chemistry studies. The goal was to Baron Müller’s opinions on Cinchona cultivation and mentioned enhance his chemistry training for later supervising the practical that while reading this author’s book, Select extra-tropical plants work carried out at the Laboratory and thus succeed the German (1881), he realised that Cinchona calisaya had also blossomed at professor. The practical studies in German laboratories would low altitude in Berwick, Australia (Möller 1887). In his papers enable him to introduce the German advancements in chemistry in published in the horticulture journal Jornal de Horticultura prática Portugal (Formosinho et al. 2013). he also quoted other German authors (Pereda 2018). He was in Germany from 1871 to 1873. He studied mineral Möller’s scientific output highlighted his connection to Germany, chemistry and applied chemistry at the University of Göttingen through his reference to the texts and works of German authors and (from 1871 to 1872) with Tollens, Hans Hübner (1837–1884) and Friedrich Wöhler (1800–1882). Afterwards, Silva performed direct contact with Germans, such as Baron de Müller. organic chemistry work at the Bonn Institute for Chemistry under the direction of Professor Friedrich August Kekulé (1829–1896) 2.3. Pharmacist Joaquim dos Santos e Silva and Otto Wallach (1847–1931) (Formosinho et al. 2013). While he 2.3.1. Pharmacist Joaquim dos Santos e Silva was studying in Bonn, he published an article in the Berichte der Deutschen Chemischen Gesellschaft titled Ueber die Brom-cam- (1842–1906): brief biography phocarbonsäure (tome 6, p. 1092-1093). He would address similar Joaquim dos Santos e Silva (Fig. 4) was born in Bruscos, topics in later papers on camphor derivatives published in the Condeixa, a small town near Coimbra, in the centre of Portugal. academic journal O Instituto. Shortly afterwards, he was hired He moved to Coimbra in 1859, where he completed secondary to supervise the practical work in the Chemistry Laboratory of education and was admitted to Coimbra University School of the Faculty of Philosophy at the University of Coimbra and was Pharmacy. In 1864 he was appointed practical work assistant to indefinitely appointed to the office in 1880 (by Decree of 23 June the Chemistry Laboratory of the University of Coimbra. It was as 1880). In 1875 he completed the pharmaceutical studies, which assistant of the Chemistry Laboratory that he met German chemist he had postponed when he moved to Germany. He took the final and professor Bernhard Christian Gottfried Tollens (1841–1918) examination in Pharmacy on 9 April 1875 (1st class pharmacist). when Tollens became the director of the Chemistry Laboratory in He was appointed full professor at the School of Pharmacy in 1869. Silva worked under Tollens’s supervision for about a year. 1902. He taught at the School of Pharmacy and was also analyt- Santos e Silva was strongly influenced by German scientists. In ical chemist in the region of Coimbra for the Forensic Medical 1870, Tollens terminated his contract and returned to Germany Council from 1899. In this position he worked with professors of to work at Göttingen University (Formosinho et al. 2013). Santos the Faculty of Medicine in forensic chemical analysis. In the field e Silva had not yet completed the pharmaceutical studies at the of toxicological chemistry, he conducted toxicological analyses Coimbra University School of Pharmacy. However, aware of the or forensic chemical analyses ordered by the courts of Coimbra scientific skills of Santos e Silva, the Dean of Coimbra University between 1878 and 1899. In 1892, Santos e Silva took part in a 400 Pharmazie 76 (2021) ORIGINAL ARTICLES well-known medicolegal case in Portugal, the Urbino de Freitas at least six different samples from São Tomé with a quinine content case. He was one of the most remarkable teachers at the School ranging between 16.1 and 47.56 g of quinine per kg of Cinchona of Pharmacy of his time. However, to excel in teaching and bark (Silva 1877, 1880; Machado 1883). He also analysed a sample research, the scientific training he undertook between 1871 and from Cabo Verde in 1874, but “the chemical reagents delivered 1873 in Germany was paramount. His field trips to Universities negative results” (Silva 1877). abroad were also important. The scientific expeditions to Berlin, In a paper published in 1877, Silva reported that the species grown Leipzig, Heidelberg, and Gießen were vital for Santos e Silva. He in São Tomé and Cabo Verde were Cinchona officinalis, Cinchona wrote profusely about chemical analysis of drinking water, thermal succirubra and Cinchona calisaya, “which are the species richest water, food, etc. In the field of hydrology, since 1876, he analysed in febrifuge principles” (Silva 1877). He conducted the prelimi- alone or in collaboration with others many waters of Portugal. He nary analyses of Cinchona bark samples from São Tomé on the published much of the results in journals such as O Instituto and initiative of Júlio Henriques (Silva 1877). The Cinchona plants Coimbra Médica. He was a pioneer in the introduction of chemical from which these bark samples had been extracted (probably from analysis in Portugal. With the knowledge he acquired in Germany the Cinchona succirubra species) had been sown in the nursery of he wrote a book called Elements of qualitative chemical anal- the Botanical Garden of Coimbra and shipped to Africa in 1869. ysis (Elementos de analyse chimica qualitativa), first published Later, in 1876, Jacintho de Sousa Ribeiro, who was a physician in in Portugal in 1874 (2nd ed. 1883; 3rd ed. 1891). This book was São Tomé, sent barks from these plants to Professor Júlio Augusto considered to be pioneer in Portugal in the field of chemical anal- Henriques (Silva 1877). Silva found that the quinine content ysis. Santos e Silva performed chemical studies on camphor and ranged from 45.76 to 47.56 g/kg Cinchona bark (4.576–4.756%). published in the journal O Instituto a paper called Chemical study The cinchonine content was only determined in one of the assays of some camphor derivatives (Estudo chimico d’alguns derivados (8.54 g/kg Cinchona bark). According to the third official Portu- da camphora) (1873-74). He had begun writing this research paper guese pharmacopoeia (1876) in force at the time, the minimum at the chemistry laboratory of Professor Kekulé in Germany in 1873 quinine content in the bark of Cinchona succirubra was 1.5% and completed it at the Chemistry Laboratory of the University of (Gomes et al. 1876). On the analysis of the first samples from São Coimbra. The work is dated with May 1874. Later, he published Tomé, Silva stated that such findings, albeit not entirely precise, another paper on the same subject, also called Chemical study of provided for “a more accurate judgement of the crop” (Silva 1877). some camphor derivatives (Estudo chimico d’alguns derivados da The chemical analyses sought to assess the quality of the Cinchona camphora) (1874-75a). He carried out research on the essence of bark from the Portuguese African colonies, and to assay whether false pepper, having published the paper Chemical studies on the the Cinchona plants farmed in Africa had the same alkaloids as essence of the false pepper (Ensaios chimicos sobre a essência da the Cinchona plants that grew in its “native country” (Silva 1877). pimenteira falsa) (1874-75b), which clearly reflects the effect of It aimed further to provide “with adequate approximation” the the time he spent in Germany. As in other papers, Santos e Silva quinine content and, secondarily, the cinchonine content in the paid tribute to German scientists with whom he worked, alluding bark of the Cinchona from the African colonies. This way, one to “the fruitful ideas of Kekulé, Oppenheim and others” (Silva could conclude about the possibility of successfully farming 1874-75b p. 209). In 1876, encouraged by the Professor of the Cinchona in the African colonies since, as Silva pointed out, “The Faculty of Philosophy and director of the Botanical Garden of vigour with which a plant grows cannot, however, be taken in all Coimbra Júlio Augusto Henriques, he performed qualitative and cases as a guarantee of the existence of the principles which moti- quantitative chemical analysis on the alkaloid content of Cinchona vate its medicinal use, even when the species cultivated are chosen bark samples from São Tomé, which resulted in a publication in among those which, in their own country, abound most in useful the journal O Instituto called Brief news on the wealth of Cinchona principles” (Silva 1877). plants cultivated on the Portuguese possessions in Africa (Breve In 1880, Silva said that he believed that his studies in 1876 were the notícia sobre a riqueza das quinas cultivadas nas possessões first to be carried out on Cinchona bark from the Portuguese posses- portuguezas da Africa, 1877). His work was of the utmost impor- sions in Africa (Silva 1880). He described further the analysis of tance for a medicinal product that was being taken as an economic two samples from São Tomé. One had been sent in September 1878 asset of unquestionable interest. We have also found by Santos e by Quintas & Irmãos, landowners on the island of São Tomé (2.5 kg Silva a book called Faktoren-Tabellen zur Ausführung chemischer of a 2.5-year-old Cinchona plant). Silva found that this Cinchona Rechnungen (…) published in 1887. bark sample had a quinine content of 40.83 g/kg Cinchona bark Santos e Silva was a full member of a scientific institution that and a cinchonine content of 1.64 g/kg Cinchona bark (4.083% and existed then, the Institute of Coimbra (Instituto de Coimbra), 0.164% respectively). The other sample provided by landowner Member of the German Chemical Society (Deutsche Chemische Gesellschaft) and Honorary Member of the Portuguese Phar- Nicolau José da Costa (also from the island of São Tomé) was from maceutical Society (Sociedade Farmacêutica Lusitana). He died a plant approximately four years old. This Cinchona bark sample February 22nd, 1906 from heart disease. had a quinine content of 41.21 g/kg Cinchona bark (4.121%) and The German influence on Joaquim dos Santos e Silva was so a cinchonine content of 2.24 g/kg Cinchona bark (0.224%). The strong that Formosinho et al. talked of a scientific genealogy in author stated that these new tests confirmed his findings in 1876; Santos e Silva which included several eminent German chemists, they showed that large-scale farming of Cinchona should arouse such that he could be considered “an early pioneer of the ‘modern the interest of landowners on the island of São Tomé (Silva 1880). Portuguese chemist’ (...), but the structures that Santos e Silva In 1883, data from the analysis of another three samples of needed to continue researching and creating a school in Coimbra Cinchona succirubra bark from São Tomé performed by Santos e did not exist, nor did his academic status allow it” (Formosinho et Silva was published. Antonio Henriques Pires had sent the samples al. 2013). These authors mentioned the names of German scientists to management of the Botanical Garden of Coimbra. The samples with whom Santos e Silva contacted and others whom he did not contained a lower quinine content (26.5 g/kg Cinchona bark, meet but influenced his work: Bernhard Tollens (1841–1918), 16.1 g/kg Cinchona bark, and 27.2 g/kg Cinchona bark), but higher Friedrich Kekulé (1829–1896), Rudolph Fittig (1835–1910), cinchonine content (Machado 1883). Heinrich Will (1812–1890), Friedrich Wöhler (1800–1882), Justus As was stated, Joaquim dos Santos e Silva, pharmacist, and Liebig (1803–1873) and Karl Kastner (1783–1857). professor at the School of Pharmacy of the University of Coimbra, obtained part of his training in chemistry in Germany, with the support of the Portuguese government. The goal was to bring to the 2.3.2. Research by Joaquim dos Santos e Silva on Cincho- country state-of-the-art techniques and to develop his know-how in na and quinine chemistry. He was hired to manage the practical work at the Chem- As manager of practical work at the Chemistry Laboratory of istry Laboratory of the University of Coimbra thanks to the success the University of Coimbra, Joaquim dos Santos e Silva analysed of his apprenticeship in Germany, as attested by the professors Cinchona bark samples from São Tomé and Cabo Verde. He tested with whom he had worked. Furthermore, he had collaborated with Pharmazie 76 (2021) 401 ORIGINAL ARTICLES

German chemist Tollens while studying pharmacy at the Univer- Gachelin G, Garner P, Ferroni E, Tröhler U, Chalmers I (2017) Evaluating Cinchona sity of Coimbra (Formosinho et al. 2013). His ties with Germany bark and quinine for treating and preventing malaria. J Royal Soc Med 110: 73–82. were thus paramount for his career at the Chemistry Laboratory Garcia JC (1988) Cartas de Bernardino de Barros Gomes a Jaime Batalha Reis. Nota in Coimbra, contributing to the recognition of the quality of his para a histó ria da Geografia em Portugal. Finisterra 23 (45): 116–126. Gomes BA (1812) Ensaio sobre o Cinchonino, e sobre a sua influencia na virtude da chemical analyses, namely the ones pertaining to Cinchona bark. quina, e d’outras cascas. In: Memorias da Academia Real das Sciencias de Lisboa, vol. 3, Parte 1, Lisboa, p. 201–216. Gomes BA, Vianna FJC, Figueira CAM, Martins JTS, Tedeschi J, Leitão CJV, 3. Conclusion Azevedo IC, Veiga JU, Lourenço AV, Aguiar AA, Silva PJ (1876) Pharmacopêa The three aforementioned Portuguese scientists played a pivotal portugueza. Edição official, Lisboa, p. 349. role in Cinchona cultivation in the Portuguese colonies. All three Gomes BB (1864) Cultura das Plantas que dão a Quina, Lisboa, p. 17-20, 85, 110-111, 113-117. were influenced by German science and scientific culture and Gomes BB (1865) Relatorio florestal sobre as matas da Machada e Valle de Zebro played important roles in Portuguese pharmacy, through their apresentado á Direcção do commercio no Ministerio das Obras Publicas em 3 de contribution to Cinchona bark cultivation and chemical analysis. Setembro de 1864, Lisboa, p. 7. Gomes wrote a book on Cinchona cultivation. He gathered infor- Guimarães B (2006) Padre Barros-Gomes: vítima da República: morto a tiro a 4 de Outubro de 1910 no Palácio de Arroios, Lisboa, p. 53-60, 70-71, 98, 110, 122-123, mation in foreign literature and published data on weather condi- 224, 369-370. tions of the possible locations for growing Cinchona in Portuguese Henriques JA (1876) A cultura das plantas que dão a quina nas possessões portu- territory. He suggested several places for farming Cinchona on guezas. O Instituto 22: 184–190. Portuguese territory and highlighted the medicinal and economic Henriques JH (1924) Adolfo F. Möller. Broteria 21: 88–90. Henry, Delondre A (1833) Sur une nouvelle substance alcaloïde découverte dans le importance of this crop, besides suggesting that the nursery in the quina jaune. Journal de Pharmacie et des sciences accessoires 19 (11): 623–625. Botanical Garden of Coimbra be used to grow Cinchona plants. Henry, Delondre (1834) A NOTE Sur une matière cristalline isolée d’un des produits Adolpho Frederico Möller was in charge of growing Cinchona de la préparation en grand du sulfate de quinine, et désignée d’abord sous le nom plants in the nurseries of the Botanical Garden of Coimbra, de quinidine. Journal de Pharmacie et des sciences accessoires 20 (3): 157–162. Hopffer FF (1876) Estado do ensaio da cultura da quina na ilha de Sancto Antão em which were planted in the Portuguese colonies. He answered the abril de 1875. O Instituto 22: 190–197. questions of farmers who were interested in growing the crop Junior DO (1885) Exploração botanica a S. Thomé e Principe. Jornal de Horticultura and called to the Portuguese government to seriously engage in Prática 16: 51–55. Cinchona cultivation. Kacprzak KM (2013) Chemistry and Biology of Cinchona Alkaloids. In: Ramawat KG, Mérillon JM (eds.) Natural Products: Phytochemistry, Botany and Metab- Joaquim dos Santos e Silva was sent by the Portuguese government olism of Alkaloids, Phenolics and Terpenes, Berlin, p. 605–641, https://doi. to Germany specifically to bring back new insight and know-how org/10.1007/978-3-642-22144-6 that would enable him to conduct chemistry demonstrations before Machado S (1882) A quina nas colonias portuguezas. Jornal da Sociedade Pharma- the students and assist teachers in their chemistry experiments. ceutica Lusitana 3:251–257. Machado S (1883) Quinas de S. Thomé. Jornal da Sociedade Pharmaceutica Lusitana By performing chemical analyses, Silva found that some of the 4:152. Cinchona bark samples from the Portuguese colonies contained Möller AF (1877) Duas palavras ácerca d’algumas especies de quinas aclimadas na a suitable quinine content, indicating that the plant could be Australia. Jornal De Horticultura Prática 8: 22–24. grown with good economic outcomes. The results of his chemical Möller AF (1878) Quinas em S. Thomé. Jornal de Horticultura Prática 9: 217–218. Möller AF (1885) Exploração botanica nas possessões portuguezas. Jornal De Horti- analyses quite possibly helped foster the expansion of Cinchona cultura Prática 16: 195–200. cultivation in the former Portuguese colonies. Möller AF (1887) Cultura das quinas em Victoria. In: Jornal da Sociedade Pharmaceu- Despite their input, the lack of government concerted, comprehen- tica Lusitana, Lisboa, 166–169. sive strategy meant that growing of this crop never reached the Moore TA. Agents Used to Treat Parasitic Infections. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J (eds.) Harrison’s Principles of Internal desired dimension. Medicine, 20e, New York. Available at: http://accessmedicine.mhmedical.com/ content.aspx?bookid=2129§ionid=192026781. Accessed September 18, 2019. Pelletier, Caventou (1820) Des Recherches chimiques sur le Quinquinas. Annales de Footnote Chimie et de Physique 15: 289–318, 337–365. 1The book Cultivation of the plants that produce Cinchona bark Pereda IG (2018) Experts florestais: Os primeiros silvicultores em Portugal (Doctoral (Cultura das plantas que dão a quina) (Gomes 1864) was commis- Dissertation, Universidade de Évora, Évora, Portugal), p. 32, 34-35, 40-41, 43, 73, 172-173. Available at: http://hdl.handle.net/10174/23656 sioned by the Portuguese Government and the book Practical Silva IFS (1867) Diccionário bibliográphico portuguez, Lisboa, vol. 8 (A-B, 1st of instructions for the culture of the plants that produce Cinchona the supplement), p. 383. bark (Instruções práticas para a cultura das plantas que dão a Silva JS (1873) Ueber die Brom-camphocarbonsäure (Aus dem chem. Institut der quina) (Henriques, 1880) was sponsored by the Portuguese Navy Universität Bonn; mitgetheilt von Aug. Kekulé). Ber Dt Pharm Ges 6: 1092–1093. Silva JS (1873-1874) Estudo chimico d’alguns derivados da camphora. O Instituto Ministry (Silva 1867; Machado 1882). 18: 220-227. Silva JS (1874) Elementos de analyse chimica qualitativa, Coimbra. Silva JS (1874-1875a) Estudo chimico d’alguns derivados da camphora. O Instituto References 20: 17-23. Andersson L (1998) A revision of the genus Cinchona (-), New Silva JS (1874-1875b) Ensaios chimicos sobre a essencia da pimenteira falsa. O Insti- York, vol. 80, p. 1. tuto 19: 209-213, 246-254. Andrés Turrión ML (2005) Las polémicas de la quina. In: Puerto Sarmiento J (ed.) Silva JS (1877) Breve notícia sobre a riqueza das quinas cultivadas nas possessões Ciencia y técnica en latinoamérica en el período virreinal, vol. 1, p. 127-149. portuguezas da Africa. O Instituto 24: 29-33. Brockway LH (2002) Science and Colonial Expansion. The Role of the British Royal Silva JS (1880) Nova analyse das quinas da Ilha de S.Thomé. Jornal de Horticultura Botanic Gardens, New Haven & London, p. 111-124. Prática 11: 238–239. Cabral C, Pereira AL, Pita JR (2015) Pharmacy, quina and quinine in Portugal, 18th- Silva JS (1883) Elementos de analyse chimica qualitativa, 2nd ed., Coimbra. 20th centuries. Circumscribere: International Journal for the History of Science Silva JS (1887) Faktoren-Tabellen zur Ausfü hrung chemischer Rechnungen mittels 16: 138–153. der von L. Meyer und K. Seubert gegebenen Atomgewichte berechnet, Braunsch- Castilho JF (1814a) Reflexõ es de José Feliciano de Castilho, sô bre um Escrito de weig. Bernardino Antonio Gomes, publicado no Investigador Portuguez em Inglaterra, Silva JS (1891) Elementos de analyse chimica qualitativa, 3rd ed., Coimbra. Num. XXII. p. 206. Jornal de Coimbra 6 (29) Parte 1: 277-287. Silva JATR (2015) A Academia Real das Ciências de Lisboa (1779-1834): ciências Castilho JF (1814b) Reflexões de José Feliciano de Castilho sôbre um Escrito de e hibridismo numa periferia europeia (Doctoral Dissertation, Universidade de Bernardino Antonio Gomes. Jornal de Coimbra 7 (35) Parte 1: 201-240. Lisboa, Lisboa, Portugal), p. 252. Available at: http://hdl.handle.net/10451/17942 Costa AF (1944) O problema das quinas, Lisboa, p. 18-19, 54-56, 92-93. Stanley C, Oaks J, Mitchell VS, Pearson GW, Carpenter CCJ (1991) Malaria: Obsta- Devy-Vareta N (1998) Les voyages de savants en Europe et le développement des cles and Opportunities, Washington, D.C., p. 37-38. idé es gé ographiques dans le Portugal du XIXe siè cle. Finisterra 33 (65): 175–183. Van der Hoogte AR, Pieters T (2014) Science in the service of colonial agro-indus- Double FJ (1820) Considérations thérapeutiques sur une nouvelle préparation de trialism: The case of cinchona cultivation in the Dutch and British East Indies, quinquina. Revue médicale 6: 130–152. 1852-1900. Stud Hist Philos Biol Biomed Sci 47: 12–22. Ferreira AM (2007) Um católico militante diante da crise nacional: Manuel Isaías Van der Hoogte AR, Pieters T (2015) Science, industry and the colonial state: a shift Abúndio da Silva (1874-1914), Lisboa, p. 319. from a German- to a Dutch-controlled cinchona and quinine cartel (1880–1920). Formosinho SJ, Herold BJ, Cardoso AC (2013) Joaquim dos Santos e Silva: um Hist Technol 31 (1): 2–36. pioneiro português da Química moderna. In: Fiolhais C, Simões C, Martins D Webb Junior JLA (2009) Humanity’s Burden. A Global History of Malaria, (eds.) História da Ciência Luso-Brasileira. Coimbra entre Portugal e o Brasil, Cambridge, p. 103-105. Coimbra, p. 207–227. Winckler FL (1847) Jahresbericht: 620. 402 Pharmazie 76 (2021)